Benzo-fused heterocycles as endothelin antagonists

ABSTRACT

The invention relates to novel benzo-fused heterocycles and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists.

The present invention relates to novel benzo-fused heterocycles of the General Formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the General Formula I and especially their use as endothelin receptor antagonists.

Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411). Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen M A et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi G M et al.: Pharmacol Rev (1994) 46:328).

Two endothelin receptors have been cloned and characterized in mammals (ET_(A), ET_(B)) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732). The ET_(A) receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein E H et al.: Drug Dev Res (1993) 29:108). In contrast, the ET_(B) receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ET_(B) receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ET_(B) receptor from smooth muscle cells exerts vasoconstricting actions (Sumner M J et al.: Brit J Pharmacol (1992) 107:858). ET_(A) and ET_(B) receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.

A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma. As a consequence, endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.

Today, only one endothelin receptor antagonist is marketed, several are in clinical trials. However, these molecules possess a number of weaknesses such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics, or safety problems (e.g. liver enzyme increases).

The inhibitory activity of the compounds of General Formula I on endothelin receptors can be demonstrated using the test procedures described hereinafter:

For the evaluation of the potency and efficacy of the compounds of the General Formula I the following tests were used:

1) Inhibition of Endothelin Binding to Membranes from CHO Cells Carrying Human ET Receptors:

For competition binding studies, membranes of CHO cells expressing human recombinant ET_(A) or ET_(B) receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu V., et al, FEBS Lett 1993; 334:210).

The assay was performed in 200 uL 50 mM Tris/HCl buffer, pH 7.4, including 25 mM MnCl₂, 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates. Membranes containing 0.5 ug protein were incubated for 2 h at 20° C. with 8 pM [¹²⁵I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1, respectively. After 2 h, the membranes were filtered on filterplates containing GF/C filters (Unifilterplates from Canberra Packard S.A. Zürich, Switzerland). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canberra Packard S.A. Zürich, Switzerland) and the filter plates counted in a microplate counter (TopCount, Canberra Packard S.A. Zürich, Switzerland).

All the test compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to interfere significantly with the binding. IC₅₀ was calculated as the concentration of antagonist inhibiting 50% of the specific binding of ET-1. For reference compounds, the following IC₅₀ values were found: ET_(A) cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ET_(B) cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3.

The IC₅₀ values obtained with compounds of General Formula I are given in Table 1.

TABLE 1 Compound of Example IC₅₀ ET_(A) [nM] IC₅₀ ET_(B) [nM] Example 27 13 126 Example 39 29 701 Example 40 8 52 Example 49 17 240 Example 50 12 507 Example 51 7 26 Example 52 11 23 Example 56 4 83 Example 58 2 29 Example 68 1 4 Example 78 3 23 Example 107 1 42 Example 111 3 10 Example 115 1 3 Example 117 61 749 Example 129 6 353 Example 167 36 947 Example 170 15 368 Example 187 18 180 Example 211 6 62 Example 213 3 29 Example 218 5 39 Example 223 7 12 2) Inhibition of Endothelin-induced Contractions on Isolated Rat Aortic Rings (ET_(A) Receptors) and Rat Tracheal Rings (ET_(B) Receptors):

The functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ET_(A) receptors) and of the contraction induced by sarafotoxin S6c on rat tracheal rings (ET_(B) receptors). Adult Wistar rats were anesthetized and exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3–5 mm rings. The endothelium/epithelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO₄ 1.2, KH₂PO₄ 1.5, NaHCO₃ 25, CaCl₂ 2.5, glucose 10) kept at 37° C. and gassed with 95% O₂ and 5% CO₂. The rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France). The rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea) were added after a 10 min incubation with the test compound or its vehicle. The functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC₅₀ induced by different concentrations of test compound. EC₅₀ is the concentration of endothelin needed to get a half-maximal contraction, pA₂ is the negative logarithm of the antagonist concentration which induces a two-fold shift in the EC₅₀ value.

The pA₂ values obtained with compounds of Formula I are given in Table 2.

TABLE 2 Compound of Example pA₂ (aortic rings) pA₂ (trachea) Example 48 8.19 6.28 Example 49 6.87 Example 50 7.35 Example 51 7.39 Example 106 8.38 6.74 Example 107 8.18 6.18 Example 115 8.55 7.56 Example 166 6.98 Example 203 7.95 6.11 Example 211 9.04 7.07

Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension, and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, pulmonary fibrosis, connective tissue diseases, stomach and duodenal ulcer, digital ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain as well as other diseases presently known to be related to endothelin.

The compounds can be administered orally, rectally, parenterally, e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol. Examples of applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.

Preferred applications are intravenous, intramuscular, or oral administrations as well as eye drops. The dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1–50 mg/kg body weight per day are considered. The preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.

The present invention relates to novel benzo-fused heterocycles of the General Formula I,

wherein

-   X represents —CH₂—CH₂—CH₂—; —NR⁹—C(═O)—CH₂—; —NR¹⁰—CH₂—CH₂—;     —C(═O)—CH₂—CH₂—; —CH₂—C(═O)—CH₂—; —O—CH₂—CH₂—; —S—CH₂—CH₂—;     —SO₂—CH₂—CH₂—; —NR⁹—C(═O)—CH₂—CH₂—; —NR¹⁰—CH₂—CH₂—CH₂—;     —O—CH₂—CH₂—CH₂—;

-   Y represents O; S; NH; N—CH₃ or CH₂; -   R¹, R², R³, R⁴ represent hydrogen; or one or two of R¹, R², R³, R⁴     idependently represent halogen; hydroxy; lower alkyl; lower     alkyloxy; lower alkyloxycarbonyl; hydroxy carbonyl; amino; lower     alkylamino; di-(lower alkyl)-amino; lower alkylcarbonylamino;     trifluoromethyl; and the others are hydrogen; -   R⁵ represents hydrogen; lower alkyl; phenyl; mono-, di-, or     tri-substituted phenyl, substituted with lower alkyl, lower     alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino,     lower alkylthio; mono-, di-substituted phenyl, substituted with     trifluoromethyl; pyridyl; benzyl or mono- or disubstituted benzyl,     substituted at the phenyl ring with lower alkyl, lower alkyloxy,     halogen, amino, lower alkylamino, di-(lower alkyl)-amino,     trifluoromethyl, lower alkylthio; -   R⁶ represents phenyl; mono-, di-, or tri-substituted phenyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio, alkylenedioxy,     ethylenoxy; mono-, di-substituted phenyl, substituted with     trifluoromethyl; pyridyl; mono- or di-substituted pyridyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower     alkylthio; pyrimidinyl; mono- or di-substituted pyrimidinyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio;     mono-substituted pyrimidinyl, substituted with trifluoromethyl; -   R⁷ represents hydrogen; lower alkyl; cycloalkyl; lower     alkylcarbonyl; benzyl; optionally substituted benzyl, substituted at     the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino,     lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower     alkylthio, alkylene-dioxy, ethylenoxy; -   R⁸ represents hydrogen; lower alkyl; lower alkylcarbonyloxy-lower     alkyl; -   R⁹ represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl;     hydroxycarbonyl-lower alkyl whereby lower alkyl can be substituted     with phenyl; lower alkyloxycarbonyl-lower alkyl whereby lower alkyl     can be substituted with phenyl; tetrazol-5-yl-lower alkyl;     2,5-dihydro-5-oxo4H-1,2,4-oxadiazol-3-yl-lower alkyl;     2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl-lower alkyl;     2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl;     2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl-lower alkyl; amino-lower alkyl;     lower alkylamino-lower alkyl; di-(lower alkyliamino-lower alkyl;     aminocarbonyl-lower alkyl; lower alkylamino carbonyl-lower alkyl;     di-(lower alkyl)-aminocarbonyl-lower alkyl; hydroxy-lower alkyl;     lower alkyloxy-lower alkyl; benzyl; mono- or di-substituted benzyl     substituted at the phenyl ring with lower alkyl, lower alkyloxy,     halogen, amino, lower alkylamino, di-(lower alkyl)-amino,     trifluoromethyl, lower alkylthio, alkylene-dioxy, ethylenoxy; -   R¹⁰ represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl;     hydroxycarbonyl-lower alkyl whereby lower alkyl can be substituted     with phenyl; lower alkyloxycarbonyl-lower alkyl whereby lower alkyl     can be substituted with phenyl; tetrazol-5-yl-lower alkyl;     2,5-dihydro-5-oxo4H-1,2,4-oxadiazol-3-yl-lower alkyl;     2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl-lower alkyl;     2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl;     2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl-lower alkyl; amino-lower alkyl;     lower alkylamino-lower alkyl; di-(lower alkyl)-amino-lower alkyl;     aminocarbonyl-lower alkyl; hydroxy-lower alkyl; lower alkyloxy-lower     alkyl; benzyl; mono- or di-substituted benzyl substituted at the     phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower     alkylthio, alkylene-dioxy, ethylenoxy; benzylcarbonyl; mono- or     di-substituted benzylcarbonyl substituted at the phenyl ring with     lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino,     di-(lower alkylyamino, trifluoromethyl, lower alkylthio,     alkylene-dioxy, ethylenoxy; lower alkylcarbonyl; phenylcarbonyl;     mono- or di-substituted phenylcarbonyl substituted with lower alkyl,     lower alkyloxy, halogen, amino, lower alkylamino, di-(lower     alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy,     ethylenoxy; lower alkylcarbonyl; lower alkyloxy-lower alkylcarbonyl;     hydroxycarbonyl-lower alkylcarbonyl; -   R¹¹ represents hydrogen; lower alkyl; cycloalkyl; lower     alkyloxy-lower alkyl; lower alkyloxycarbonyl; hydroxycarbonyl; lower     alkyloxycarbonyl-lower alkyl; hydroxycarbonyl-lower alkyl; phenyl;     mono- or di-substituted phenyl substituted with lower alkyl, lower     alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino,     trifluoromethyl, lower alkylthio; benzyl; mono- or di-substituted     benzyl substituted at the phenyl ring with lower alkyl, lower     alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino,     lower alkylthio; -   R¹² represents hydrogen; lower alkyl; cycloalkyl; lower     alkyloxy-lower alkyl; phenyl; mono- or di-substituted phenyl     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkylkamino, trifluoromethyl, lower alkylthio; -   R¹³ represents hydrogen; lower alkyl; cycloalkyl; lower     alkyloxy-lower alkyl; -   R¹⁴ represents hydrogen; lower alkyl; cycloalkyl; lower     alkyloxy-lower alkyl; phenyl; mono- or di-substituted phenyl     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower     alkylthio; benzyl; mono- or di-substituted benzyl substituted at the     phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio; lower     alkyloxycarbonyl; hydroxycarbonyl; lower alkyloxycarbonyl-lower     alkyl; hydroxycarbonyl-lower alkyl lower; aminocarbonyl;     alkylaminocarbonyl; di-(lower alkyl)-aminocarbonyl; -   R¹⁵ represents hydrogen; lower alkyl; cycloalkyl; lower     alkyloxy-lower alkyl; lower alkyloxycarbonyl; hydroxycarbonyl; lower     alkyloxycarbonyl-lower alkyl; hydroxycarbonyl-lower alkyl;     aminocarbonyl; lower alkylaminocarbonyl; di-(lower     alkyl)-aminocarbonyl;     and optically pure enantiomers, mixtures of enantiomers such as     racemates, pure diastereomers, mixtures of diastereomers,     diastereomeric racemates, mixtures of diastereomeric racemates and     the meso-forms and pharmaceutically acceptable salts thereof.

In the definitions of the General Formula I if not otherwise stated—the expression lower alkyl or lower alkyloxy means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms. Examples of lower alkyl and lower alkyloxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy. Lower alkylene-dioxy-groups are preferably methylene-dioxy, ethylene-dioxy, propylene-dioxy and butylene-dioxy groups. Examples of lower alkanoyl-groups are acetyl, n-propanoyl, i-propanoyl, n-butanoyl, i-butanoyl, sec-butanoyl and t-butanoyl. Lower alkenyl and lower alkynyl means groups like ethenyl, propenyl, butenyl, 2-methyl-propenyl, and ethynyl, propynyl, butynyl, pentynyl, 2-methyl-pentynyl etc. Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like. The expression cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms , e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and lower alkyloxy-lower alkyl groups.

It is understood that the substituents outlined relative to the expressions alkyl and cycloalkyl have been omitted in the definitions of the General Formula I in claims 1 to 8 for clarity reasons but the definitions in Formula I and in claims 1 to 8 should be read as if they are included therein.

The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the like or in case the compound of Formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc.

The compounds of the General Formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and also in the meso-form. The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc.

Because of their ability to inhibit endothelin binding, the compounds of the General Formula I and their pharmaceutically acceptable salts may be used for the treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, as well as other diseases presently known to be related to endothelin.

These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories. These compounds may also be administered in intramuscular, parenteral or intravenous form, e.g. in form of injectable solutions.

These pharmaceutical compositions may contain the compounds of Formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of solutions and syrups e.g. water, polyols, saccharose, glucose etc. are used. Injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols etc.

The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, antioxidants etc.

The compounds of Formula I may also be used in combination with one or more other therapeutically useful substances e.g. α- and β-blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol etc.; vasodilators like hydralazine, minoxidil, diazoxide, flosequinan etc.; calcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil, nifedipine etc.; ACE-inhibitors like cilazapril, captopril, enalapril, lisinopril etc.; potassium activators like pinacidil etc.; angiotensin II antagonists; diuretics like hydrochlorothiazide, chlorothiazide, acetolamide, bumetanide, furosemide, metolazone, chlortalidone etc.; sympatholitics like methyldopa, clonidine, guanabenz, reserpine etc.; and other therapeutics which serve to treat high blood pressure or any cardiac disorders.

The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given daily in oral form should be between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.

Preferred compounds of General Formula I are the compounds wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and X are as defined in General Formula I, and wherein

-   R⁶ represents pyrimidinyl; mono- or di-substituted pyrimidinyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio;     mono-substituted pyrimidinyl, substituted with trifluoromethyl, -   and Y represents oxygen,     and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of General Formula I wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X and Y are as defined in General Formula I, and wherein

-   R⁵ represents phenyl; mono-, di-, or tri-substituted phenyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio; mono-,     di-substituted phenyl, substituted with trifluoromethyl     and pharmaceutically acceptable salts thereof.

A third group of preferred compounds are compounds of General Formula I wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and Y are as defined in General Formula I, and wherein

-   X represents —NR⁹—C(═O)—CH₂—     and pharmaceutically acceptable salts thereof.

A fourth group of preferred compounds are compounds of General Formula I wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X and Y are as defined in General Formula I, and wherein

-   R² represents hydrogen     and pharmaceutically acceptable salts thereof.

A group of more preferred compounds are compounds of General Formula I wherein R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X and Y are as defined in General Formula I, and wherein

-   R¹ represents hydrogen and -   R² represents hydrogen and -   R⁴ represents hydrogen     and pharmaceutically acceptable salts thereof.

A group of particulary preferred compounds are compounds of General Formula I wherein R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X and Y are as defined in General Formula I, and wherein

-   R¹ represents hydrogen and -   R² represents hydrogen and -   R³ represents hydrogen or halogen and -   R⁴ represents hydrogen and     and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of General Formula I wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ are as defined in General Formula I, and wherein

-   R¹ represents hydrogen and -   R² represents hydrogen and -   R³ represents hydrogen or halogen and -   R⁴ represents hydrogen and -   R⁵ represents phenyl; mono-, di-, or tri-substituted phenyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio; mono-,     di-substituted phenyl, substituted with trifluoromethyl and -   R⁶ represents pyrimidinyl; mono- or di-substituted pyrimidinyl,     substituted with lower alkyl, lower alkyloxy, halogen, amino, lower     alkylamino, di-(lower alkyl)-amino, lower alkylthio;     mono-substituted pyrimidinyl, substituted with trifluoromethyl and -   R⁷ represents hydrogen and -   R⁸ represents hydrogen and -   R⁹ represents lower alkyl; lower alkenyl; lower alkynyl;     hydroxycarbonyl-lower alkyl whereby lower alkyl can be substituted     with phenyl; lower alkyloxycarbonyl-lower alkyl whereby lower alkyl     can be substituted with phenyl; hydroxy-lower alkyl; lower     alkyloxy-lower alkyl; tetrazol-5-yl-lower alkyl;     2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl;     2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl-lower alkyl;     2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl;     2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl-lower alkyl; benzyl; mono- or     di-substituted benzyl substituted at the phenyl ring with lower     alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower     alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy,     ethylenoxy, and -   X represents —NR⁹—C(═O)—CH₂— and -   Y represents oxygen     and pharmaceutically acceptable salts thereof.

Especially preferred compounds are:

-   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((6S*)-1-methyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic     acid; -   (±)-(S*)-(4,6dimethyl-pyrimidin-2-yloxy)-((6S*)-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic     acid; -   (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid; -   (±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic     acid methyl ester; -   (±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-[(5S*)-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid; -   (±)-(S*)-((5S*)-1-Carboxymethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-1-(3,5-Dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(1H-tetrazol-5-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic     acid methyl ester; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(4-trifluoromethyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-1-(3-chloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-{(5S*)-1-[2-(1-methyl-1H-indol-3-yl)-ethyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl}-acetic     acid; -   (±)-(S*)-[(5S*)-1-(2-chloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-2-oxo-1-phenethyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(4-trifluoromethoxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-1-(2,6-difluoro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-{(5S*)-1-[2-(2-methoxy-ethoxy)-ethyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl}-acetic     acid; -   (±)-(S*)-[(5S*)-1-(2,4-difluoro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,3,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trimethyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,3,4-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-1-(4-butyl-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-1-(2,6-dichloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-2-oxo-1,5-diphenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid; -   (±)-4-{(5S*)-5-[(S*)-carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic     acid methyl ester; -   (±)-(S*)-(4,6-diethyl-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-diethyl-pyrimidin-2-yloxy)-[(5S*)-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-diethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-4-methyl-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-7-chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(3,5-dimethoxy-phenoxy)-acetic     acid; -   (±)-(1S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(1S*)-[(5S*)-7-chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(1S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-7-chloro-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-1-(4-butylbenzyl)-7-chloro-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-7-chloro-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-7-chloro-1-(2,6-dichloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-diethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-m-tolyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-2-oxo-1-(2,4,6-trimethyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-2-oxo-1-(2,3,4-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-5-(3-methoxy-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-methoxy-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-1-carboxymethyl-5-(3-methoxy-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-methoxy-phenyl)-2-oxo-1-(2,3,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-5-biphenyl-3-yl-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-5-biphenyl-3-yl-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-((5S*)-5-biphenyl-3-yl-1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-5-biphenyl-3-yl-2-oxo-1-(2,3,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(4-fluoro-3-methyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid; -   (±)-(S*)-[(5S*)-5-butyl-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(R*)-[(5S*)-7-chloro-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S*)-1-(4-butyl-benzyl)-5-(3-butyl-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-[(5S)-5-(3-butyl-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)acetic     acid; -   (±)-(S*)-[(5S*)-5-(3-Butyl-phenyl)-1-(2,6-dichloro-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid; -   (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid dimethylcarbamoylmethyl ester;     and pharmaceutically acceptable salts thereof.

Compounds of the General Formula I of the present invention can be prepared according to the general sequence of reactions outlined below. For simplicity and clarity reasons sometimes only parts of the synthetic possibilities which lead to compounds of General Formula I are described.

In case R⁷ does not represent a hydrogen atom, the desired compounds of General Formula I can be prepared by reacting a compound of Formula II with an alkylating or acylating agent R⁷—G¹, wherein G¹ represents a reactive group such as a chlorine, bromine, or an iodine atom. For final products of General Formula I wherein R⁷ does not represent a hydrogen atom and wherein R⁸ represents a hydrogen atom, this step is preferably performed with intermediates where R⁸ represents an alkyl group (e.g methyl) which is then cleaved in a second step in water in the presence of either a base or an acid in the presence or absence of additional solvents (e.g. methanol, THF, etc.).

In case R⁷ does represent a hydrogen atom, the desired compounds of General Formula I are directly obtained by reacting a compound of Formula III as mentioned below.

The desired compounds of Formula II can be prepared by reacting a compound of the Formula III with water or an alcohol R⁸—OH in the presence of either a base (e.g LiOH, NaOH, KOH, triethylamine, DBU, DBN, etc.) or an acid (e.g. HCl, TFA) in the presence or absence of additional solvents such as methanol, ethanol, THF, dioxane, etc, at temperatures between zero and 100° C.

In case Y represents O, S or NH and R⁶ represents phenyl or substituted phenyl, compounds of Formula III are prepared by reacting a compound of Formula IV with a compound of Formula V in the presence of a base (e.g. triethylamine etc) and an activating agent such as bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP), phenyl N-methyl-N-phenylphosphoramidochloridate or 2-chloro-N-methylpyridinium iodide or the acide chloride of compound of Formula V in a solvent such as DCM, THF, etc. or mixtures thereof, at temperatures between zero and 80° C., as described in the literature: D. R. Shridhar, B. Ram, V. L. Narayana, Synthesis, (1982), 63–65; D. R. Shridhar, B. Ram, V. L. Narayana, A. K. Awasthi, G. J. Reddy, Synthesis, (1984), 846–847; S. G. Amin, R. D. Glazer, M. S. Manhas, Synthesis, (1979), 210–213; M. S. Manhas, S. G. Amin, R. D. Glazer, J. Heterocyclic Chem., 16, (1979), 283–288; M. Miyake, N. Tokutake, M. Kirisawa, Synthesis, 14, (1984), 353–362, S. D. Sharma, A. Saluja, S. Bhaduri, Indian J. Chem. Sect. B, 39, (2000), 156–159. If Y represents NH, the compound of Formula V is previously protected with p-methoxy-benzyloxycarbonyl, for example, as described in U.S. Pat. No. 3,560,489, (1971); the obtained compound of Formula III is deprotected according to standard methodology (e.g. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Edition, Wiley New York, 1999; P. J. Kocienski, Protecting Groups, Thieme Stuttgart, 1994). In case Y represents N—CH₃ and R⁶ phenyl or substituted phenyl or Y represents CH₂ and R⁶ phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl or substituted pyrimidinyl compounds of Formula III are prepared by reacting a compound of Formula IV with an ester derivative of compound of Formula V in analogy to procedures described by J. W. Clader, D. A. Duane, M. A. Caplen, M. S. Domalski, S. Dugar, J. Med. Chem., 39, (1996), 3684–3693 and F. H. van der Steen, H. Kleijn, J. T. B. H. Jastrzebski, G. van Koten, Tetrahedron Letters, 30, (1989), 765–768.

Compounds of Formula IV are prepared according to procedures given in the literature: e.g. by N. H. Martin, C. W. Jefford in Helv. Chim. Acta, 75, (1982), 762–774; M. G. Bock, R. M. DiPardo, B. E. Evans, K. E. Rittle, D. F. Veber, R. M. Freidinger, J. Hirshfield, J. P. Springer, J. Org. Chem., 52, (1987); by H. Umemiya, H. Fukasawa, M. Ebisawa, L. Eyrolles, E. Kawachi, G. Eisenmann, H. Gronemeyer, Y. Hashimoto, K. Shudo, H. Kagechika, J. Med. Chem., 40, (1997); R. C. Effland, G. C. Helsey, J. J. Tegeler, J. Heterocyclic Chem. 19 (1982), 537–539 3232–3239.; J. B. Bremner, E. J. Browne, I. W. K. Gunawardana, Aust. J. Chem. 37 (1984) 129–141; E. J. Trybulski, R. I. Fryer, E. Reeder, A. Walser, J. Blount, J. Med. Chem. 26 (1983), 1596–1601; E. J. Trybuiski, E. Reeder, J. F. Blount, A. Walser, R. I. Fryer, J. Org. Chem. 47 (1982), 2441–2447; E. J. Trybulski, R. I. Fryer, E. Reeder, S. Vitone, L. Todaro, J. Org. Chem. 51 (1986), 2191–2202; E. J. Trybulski, L. E. Benjamin, J. V. Earley, R. I. Fryer, N. W. Gilman et al., J. Med. Chem. 26 (1983), 1589–1596; J. B. Hester, A. D. Rudzik, B. V. Kamdar, J. Med. Chem. 14 (1971), 1078–1081; A. Walser, R. I. Fryer, J. Heterocyclic Chem. 20 (1983), 551–558; A. Walser, L. E. Benjamin, T. Flynn, C. Mason, R. Schwartz, R. I. Fryer, J. Org. Chem. 43 (1978), 936–944; R. I. Fryer, J. V. Earley, N. W. Gilman, W. Zally, J. Heterocyclic Chem. 13 (1976), 433–437; R. I. Fryer, Z.-Q. Gu, C.-G. Wang, J. Heterocyclic Chem. 28 (1991), 1661–1669; M. Gall, B. V. Kamdar, J. Org. Chem. 46 (1981), 1575–1585; A. Walser, R. F. Lauer, R. I. Fryer, J. Heterocyclic Chem. 15 (1978), 855–858; N. W. Gilman, P. Rosen, J. V. Earley, C. M. Cook, J. F. Blount, L. M. Todaro, J. Org. Chem. 58 (1993), 3285–3298; A. Walser, T. Flynn, C. Mason, R. I. Fryer, J. Heterocyclic Chem. 23 (1986) 1303–1314; G. Romeo, M. C. Aversa, P. Giannetto, P. Ficarra, M. G. Vigorita, Org. Magn. Reson., 15, (1981), 33–36; H. J. Breslin, M. J. Kukla, D. W. Ludovici, R. Mohrbacher, W. Ho, J. Med. Chem., 38, (1995), 771–793.

Compounds of Formula V are prepared using standard methodology (e.g. J. March, Advanced Organic Chemistry, 3^(rd) Edition, Wiley New York, 1985) e.g. from chloro-, bromo-, or iodo acetic acid and a compound R⁶—YH in the presence of a base, or by reacting a compound of Formula VI, wherein P¹ represents a protecting group such as lower alkyl, with a compound of Formula VII, wherein G¹ represents a reactive group such as a chlorine atom, a bromine atom, or a methyl-sulfonyl group, in the presence of a base (e.g. triethylamine, K₂CO₃, NaH) in a solvent such as THF, DMF, etc., and subsequent ester cleavage.

In case Y represents O, S NH or N—CH₃ and R⁶ represents a pyridinyl, a substituted pyridinyl, a pyrimidinyl or a substituted pyrimidinyl group compounds of Formula III are preferably prepared by reacting a compound of Formula VIII with a compound of Formula VII in the presence of a base (e.g. K₂CO₃, triethylamine, NaH) in a solvent such as acetone, DMF, THF, DCM or mixtures thereof at temperatures between 0 and 80° C.

Compounds of Formula VIII are prepared by cleavage of the protecting group P² in compounds of Formula IX, which in turn are prepared by reacting a compound of Formula IV with a compound of Formula X under conditions as described for the reaction of a compound of Formula IV with a compound of Formula V. A suitable protecting group P² is selected according to the nature of Y. For the cleavage of such a protecting group P², standard methodology is applied (e.g. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Edition, Wiley New York, 1999; P. J. Kocienski, Protecting Groups, Thieme Stuttgart, 1994). A benzyl protecting group, for example, is a preferred protecting group for compounds of Formula I wherein Y represents oxygen. For compounds of Formula I wherein Y represents NH a phthalimide protecting group for example is preferred, as described by C. Hubschwerlen, G. Schmid, Helv. Chim. Acta 66 (1983), 2206–2209. For compounds of Formula I wherein Y represents N—CH₃ a benzyloxycarbonyl protecting group for example is preferred. A dimethoxytriphenylmethyl or a triphenylmethyl protecting group, for example, is preferred for compounds of Formula I wherein Y represents a sulfur.

EXAMPLES

The following examples illustrate the invention but do not at all limit the scope thereof. All temperatures are stated in ° C.

All compounds were characterized by ¹H-NMR (300 MHz) and occasionally by ¹³C-NMR (75 MHz) (Varian Oxford, 300 MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet; m=multiplet, br=broad, coupling constants are given in Hz), by LC-MS¹ (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6×50 mm, Develosil RP Aqueous, 5 μm, 120A, gradient: 5–95% acetonitrile in water, 1 min, with 0.04% trifluoroacetic acid, flow: 4.5 ml/min) or LC-MS² (Waters Micromass; ZMD-platform with ESI-probe with Alliance 2790 HT and DAD 996, column: 2×30 mm, Gromsil ODS4, 3 μm, 120A; gradient: 0–100% acetonitrile in water, 6 min, with 0.05% formic acid, flow: 0.45 ml/min), t_(R) is given in min; by tlc (tlc-plates from Merck, Silica gel 60 F₂₅₄) and occasionally by melting point. Some compounds were purified by preparative HPLC (two Varian SD-1 prep star pumps, PL-ELS 1000 detector, column 60×21.2 mm, Phenomenex AQUA, 5 μm, gradient: 10–95% acetonitrile in water, 3.5 min, with 0.5% formic acid) or by MPLC (Labomatic MD-80-100 pump, Linear UVIS-201 detector, column: 350×18 mm, Labogel-RP-18-5s-100, gradient: 10% methanol in water to 100% methanol).

List of Abbreviations:

-   aq. aqueous -   atm atmosphere -   CyHex cyclohexane -   DBN 1,5-Diazabicyclo[4.3.0]non-5-ene -   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene -   DCM dichloromethane -   DMAP 4-dimethylaminopyridine -   DME 1,2-dimethoxyethane -   DMF dimethylformamide -   DMSO dimethylsulfoxide -   EA ethyl acetate -   Hex hexane -   HV high vacuum conditions -   MCPBA m-chloroperbenzoic acid -   min minutes -   THF tetrahydrofuran -   rt room temperature -   sat. saturated -   t_(R) retention time -   tlc thin layer chromatography

Example 1

-   a) 1-Phenyl-3,4-dihydro-isoquinoline was prepared according to a     procedure given in the literature (I. Lantos et al. J. Org. Chem. 51     (1986), 4147–4150). ¹H-NMR (300 MHz, CDCl₃): 2.78–2.85 (m, 2H),     3.82–3.89 (m, 2H), 7.21–7.30 (m, 3H), 7.36–7.46 (m, 4H), 7.58–7.63     (m, 2H). -   b) A mixture of 3,5-dimethoxy-phenol (5 g, 32.4 mmol), ethyl     bromoacetate (3.6 ml, 32.4 mmol) and potassium carbonate (6.7 g,     48.5 mmol) in acetone (50 ml) is refluxed for 5 h. The mixture is     filtered and the fitrate evaporated to give     (3,5-dimethoxy-phenoxy)-acetic acid ethyl ester (8 g) as a     colourless oil. ¹H-NMR (300 MHz, CDCl₃): 1.30 (t, J=7, 3H), 3.75 (s,     3H), 4.27 (d, J=7, 2H), 4.56 (s, 2H), 6.08 (d, J=2, 2H), 6.12 (t,     J=2, 1H). -   c) To a solution of (3,5-dimethoxy-phenoxy)-acetic acid ethyl ester     (7.8 g, 32.5 mmol) in THF (50 ml) and methanol (20 ml) is added     lithium hydroxyde monohydrate (3.4 g, 81.0 mmol), dissolved in water     (50 ml), at 0° C. The solution is stirred at rt for 4 h, then poured     into 1 M aq. HCl. The aqueous phase is extracted twice with EA. The     organic phase is dried over Na₂SO₄ and evaporated to give     (3,5-dimethoxy-phenoxy)acetic acid (6.75 g) as an orange solid.     ¹H-NMR (300 MHz, CDCl₃): 3.71 (s, 3H), 4.51 (s, 2H), 6.06–6.08 (m,     3H). LC-MS²: t_(R)=4.38 min, [M+1]⁺=241.27. -   d) A solution of 1-phenyl-3,4-dihydro-isoquinoline (500 mg, 2.41     mmol), (3,5-dimethoxy-phenoxy)-acetic acid (511 mg, 2.41 mmol) and     triethylamine (1.34 ml, 9.64 mmol) in DCM (12 ml) is cooled to 5° C.     and then treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride     (460 mg, 1.81 mmol). The mixture is stirred at 0–5° C. for 5 h     before a second portion of bis(2-oxo-3-oxazolidinyl)phosphinic     chloride (460 mg, 1.81 mmol) is added. The mixture is stirred at rt     for 1.5 h before it is diluted with DCM, washed with sat. aq. NaHCO₃     and brine. The organic phase is dried over Na₂SO₄ and evaporated.     The crude product is purified by column chromatography on silica gel     eluting with heptane:EA 5:1 to furnish     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (843 mg) as a colourless foam. ¹H-NMR (300 MHz, CDCl₃): 2.58–2.71     (m, 1H), 2.76–2.85 (m, 1H), 3.66–3.74 (m, 2H), 3.67 (s, 6H), 5.51     (s, 1H), 6.06–6.08 (m, 2H), 6.11–6.14 (m, 1H), 7.17–7.20 (m, 1H),     7.28–7.43 (m, 7H), 7.50–7.54 (m, 1H). -   e) To a solution of     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-1,4,5,9b-tetrahydro-azeto[2,1-a]iso-quinolin-2-one     (1.8 g, 4.48 mmol) in THF (20 ml) and ethanol (10 ml) a solution of     LiOH.H₂O (2.26 g, 53.8 mmol) in water (15 ml) is added. The mixture     is stirred at 70° C. for 4 h before it was neutralised with 2 M HCl.     Upon evaporation of the organic solvents a white precipitate forms.     The precipitate is collected and desalted by HPL-chromatography on     RP-C₁₈ silica gel. This furnishes     (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic     acid (1.1 g) as a white solid. LC-MS²: t_(R)=3.85 min,     [M+1]⁺=420.34, [M−1]⁻=418.28. ¹H-NMR (300 MHz, D₆-DMSO): 2.82–2.91     (m, 2H), 2.95–3.05 (m, 1H), 3.38–3.44 (m, 1H), 3.64 (s, 6H), 4.98     (s, 1H), 6.02 (t, J=2, 1H), 6.16 (d, J=2, 2H), 7.08–7.36 (m, 7H),     7.54–7.59 (m, 2H).

Example 2

To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in THF (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before methyliodide (30 μl, 0.477 mmol) is added. Stirring at 55° C. is continued for another 16 h. The mixture is diluted with EA and extracted with water. The aqueous phase is acidified with 2 N HCl and extracted with EA. The EA-phase is dried over Na₂SO₄ and evaporated. The crude product is purified by prep. HPLC on Rp-C₁₈-silica gel to give (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-methyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (139 mg) as a white powder. LC-MS²: t_(R)=4.03 min, [M+1]⁺=434.34, [M−1]⁻=432.32.

Example 3

To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in acetonitrile (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before ethyliodide (95 μl, 1.19 mmol) is added. Stirring at 55° C. is continued for another 16 h before water is added (about 200 μl). The solvent is removed under reduced pressure and the crude product is purified by prep. HPLC on Rp-C₁₈ silica gel to furnish (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-ethyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (58 mg) as a white solid. LC-MS²: t_(R)=4.20 min, [M+1]⁺=448.39, [M−1]⁻=446.34.

Example 4

A solution of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (100 mg, 0.238 mmol, Example 1), DMAP (6 mg, 0.048 mmol) and acetic anhydride (27 μl, 0.286 mmol) in pyridine (2 ml) is stirred at rt for 2.5 h. The reaction mixture is diluted with DCM, washed with 1 N aq. HCl. The organic phase is dried over Na₂SO₄ and evaporated. The crude product is purified by column chromatography on silica gel eluting with heptane:EA 1:1, EA, then methanol to give (±)-((1S*)-2-acetyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-((S*)-3,5-dimethoxy-phenoxy)-acetic acid (57 mg) as yellow solid. LC-MS²: t_(R)=4.57 min, [M+1]⁺=462.38.

Example 5

To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (60 mg, 0.143 mmol, Example 1) in THF (5 ml) Hünig's base (122 μl, 0.715 mmol) followed by chlorotrimethylsilane (22 μl, 0.172 mmol) is added at 5° C. The mixture is stirred at 55° C. for 3 h before phenylacetylchloride (29 μl, 0.215 mmol) is added. Stirring is continued at rt for 2 h before water (approx. 200 μl) is added. The mixture is diluted with DCM, washed twice with 2 N aq. HCl. The organic phase is dried over Na₂SO₄ and evaporated. The crude product is purified by prep. HPLC on Rp-C₁₈ silica gel to give (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-2-phenylacetyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (36 mg) as a white powder. LC-MS¹: t_(R)=0.98 min, [M+1]⁺=538.13.

Example 6

(±)-(S*)-(3,5-dimethoxy-phenoxy)-{(1S*)-2-[2-(4-methoxy-phenyl)-acetyl]-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl}-acetic acid (74 mg) is prepared in analogy to Example 5 starting from (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (90 mg, 0.214 mmol, Example 1) and 4-methoxyphenylacetyl chloride (49 μl, 0.321 mmol). LC-MS²: t_(R)=5.25 min, [M+1]⁺=568.43, [M−1]⁻=566.51.

Example 7

(±)-(S*)-(3,5-dimethoxy-phenoxy)-{(1S*)-2-[2-(3,5-dimethoxy-phenyl)-acetyl]-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl}-acetic acid (77 mg) is prepared in analogy to Example 5 starting from (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (90 mg, 0.214 mmol, Example 1) and 3,5-dimethoxyphenylacetyl chloride (83 mg, 0.385 mmol). LC-MS²: t_(R)=5.23 min, [M+1]⁺=598.35, [M−1]⁻=596.29.

Example 8

-   a) 4,6-dimethoxy-2-methylsulfanyl-pyrimidine is synthetized from     4,6-dichloro-2-(methylthio)pyrimidine as described by S. Batori, A.     Messmer, J. Heterocyclic Chem., 31, (1994), 1041–1046. ¹H-NMR (300     MHz, CDCl₃): 2.53 (s, 3H), 3.92 (s, 6H), 5.17 (s, 1H). -   b) To 4,6-dimethoxy-2-methylsulfanyl-pyrimidine (2.67 g, 14.3 mmol),     dissolved in DCM (20 ml), is added 39% peracetic acid in acetic acid     (5.37 ml, 31.5 mmol) at 0° C. and the solution is stirred for 3 h at     rt. The solution is poured into sat. aq. NaHCO₃. The aqueous phase     is extracted twice with DCM. The organic phase is washed once with     sat. aq. NaHCO₃, once with sat. aq. NaCl, dried over Na₂SO₄ and     evaporated to give 2-methanesulfonyl-4,6-dimethoxy-pyrimidine     (2.8 g) as a white solid. ¹H-NMR (300 MHz, CDCl₃): 3.32 (s, 3H),     4.03 (s, 6H), 6.18 (s, 1H). -   c) At 5–10° C. a solution of hydroxy-acetic acid methyl ester (4.13     g, 45.8 mmol) in THF (40 ml) is slowly added to a suspension of NaH     (1.83 g 60% in mineral oil, 45.8 mmol) in THF (60 ml). After     completion of the addition, the mixture is stirred at rt for 20 min     before a solution of 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (5     g, 22.9 mmol) in THF (40 ml) is added. Stirring is continued at rt     for 40 min before the mixture is diluted with EA and washed with     sat. aq. NaHCO₃ and brine. The organic phase is dried over MgSO₄,     evaporated and dried under HV to give     (4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid methyl ester (5.99 g)     as a colourless oil which was used without further purification.     ¹H-NMR (300 MHz, CDCl₃): 3.75 (s, 3H), 3.88 (s, 6H), 4.85 (s, 2H),     5.72 (s, 1H). -   d) At 10° C., a solution of LiOH.H₂O (2.88 g, 68.7 mmol) in water     (37 ml) is slowly added to a solution of     (4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid methyl ester (5.99 g,     22.9 mmol) in THF (63 ml) and methanol (25 ml). The mixture is     stirred at rt for 1 h before it is diluted with EA and extracted     twice with water and sat. aq. NaHCO₃. The aqueous phase is acidified     with 37% aq. HCl and extracted three times with EA. The organic     phase is dried over MgSO₄, evaporated and dried under HV to give     (4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid (3.51 g) as a white     powder. ¹H-NMR (300 MHz, CDCl₃): 3.90 (s, 6H), 4.90 (s, 2H), 5.76     (s, 1 H). -   e) Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.76 g, 6.9 mmol)     is added to an ice-cold solution of     1-phenyl-3,4-dihydro-isoquinoline (950 mg, 4.6 mmol, Example 1) and     (4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid (982 mg, 4.6 mmol) in     DCM (25 ml). The mixture is allowed to slowly warm to rt and is     stirred overnight before it is diluted with DCM and washed with sat.     aq. NaHCO₃. The organic phase is dried over MgSO₄ and evaporated.     The crude product is purified by column chromatography eluting with     heptane:EA 5:1 to 2:1 to furnish     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (252 mg) as a white solid. LC-MS²: t_(R)=5.07 min, [M+1]⁺=404.33. -   f) To a solution of     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (100 mg, 0.248 mmol) in THF (4 ml) is added 6 N aq. HCl (6 ml). The     resulting solution is stirred at rt for 17 h, then at 70° C. for     2 h. The solvent is removed under reduced pressure, the water is     coevaporated with toluene. The oily residue is precipitated twice     from diethylether, the solid material is dissolved in DCM and washed     with water. The organic phase is dried over Na₂SO₄ and evaporated to     give     (±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic     acid (90 mg) as yellow oil. LC-MS²: t_(R)=3.76 min, [M+1]⁺=422.37.

Example 9

-   a) 1-(3,4-Dimethoxy-phenyl)-3,4-dihydro-isoquinoline was prepared in     analogy to a literature procedure (I. Lantos et al. J. Org. Chem. 51     (1986), 4147–4150). ¹H-NMR(300 MHz, CDCl₃):3.00–3.17 (m, 2H),     3.58–3.62 (m, 1H), 3.88 (s, 3H), 3.92–3.98 (m, 4H), 6.82–6.98 (m,     2H), 7.20–7.26 (m, 1H), 7.38–7.46 (m, 1H), 7.52–7.58 (m, 1H),     7.62–7.70 (m, 2H). LC-MS²: t_(R)=2.68 min, [M+HCOOH]⁺=268.29. -   b) Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (400 mg, 1.57 mmol)     is added to an ice-cold solution of     1-(3,4-dimethoxy-phenyl)-3,4-dihydro-isoquinoline (530 mg, 2.18     mmol) and (3,5-dimethoxy-phenoxy)-acetic acid (463 mg, 2.18 mmol,     Example 1) in DCM (12 ml). The mixture is allowed to slowly warm to     rt and is stirred for 52 h before a second portion of     bis(2-oxo-3-oxazolidinyl)phosphinic chloride (432 mg, 1.70 mmol) is     added. Stirring is continued for 16 h. The mixture is diluted with     DCM and washed with sat. aq. NaHCO₃. The organic phase is dried over     MgSO₄ and evaporated. The crude product is purified by column     chromatography eluting with heptane:EA 2:1 to furnish     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-9b-(3,4-dimethoxy-phenyl)-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (730 mg) as a yellow foam. LC-MS²: t_(R)=4.95 min, [M+1]⁺=462.36. -   c) A solution of     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-9b-(3,4-dimethoxy-phenyl)-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (100 mg, 0.216 mmol) in 1 ml dioxane is treated with 6 N aq. HCl.     The mixture is stirred at 70° C. for 18 h before the solvent is     evaporated. The crude product is purified by MPL-chromatography on     Rp-C₁₈ silica gel to give     (±)-(S*)-(3,5-dimethoxy-phenoxy)-[(1S*)-1-(3,4-dimethoxy-phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetic     acid (47 mg) as a beige solid. LC-MS²: t_(R)=3.75 min,     [M+1]⁺=480.41.

Example 10

-   a) 1-Benzyl-3,4-dihydro-isoquinoline is prepared according to a     procedure given in the literature (N. H. Martin, C. W. Jefford,     Helv. Chim. Acta 65 (1982), 762–774). ¹H-NMR (300 MHz, CDCl3): 2.72     (t, J=7.4, 2H), 3.77 (t, J=7.4, 2H), 4.09 (s, 2H), 7.14–7.38 (m,     8H), 7.47 (d, J=7.5, 1H). LC-MS²: t_(R)=2.86 min, [M+1]⁺=222.23. -   b) Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.58 g, 6.2 mmol)     is added in two portions to an ice-cold solution of     1-benzyl-3,4-dihydro-isoquinoline (920 mg, 4.15 mmol) and     (3,5-dimethoxy-phenoxy)-acetic acid (882 mg, 4.15 mmol, Example 1)     in DCM (20 ml). The mixture is allowed to slowly warm to rt and is     stirred for 4 h before it is diluted with DCM and washed three times     with sat. aq. NaHCO₃. The aq. phase is extracted with additional     DCM. The organic phase is dried over MgSO₄ and evaporated. The crude     product is purified by column chromatography eluting with heptane:EA     2:1 to furnish     (±)-(1S*,9bS*)-9b-benzyl-1-(3,5-dimethoxy-phenoxy)-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (414 mg) as a yellow foam. LC-MS²: t_(R)=5.59 min, [M+1]⁺=416.19. -   c) A solution of     (±)-(1S*,9bS*)-9b-benzyl-1-(3,5-dimethoxy-phenoxy)-1,4,5,9b-tetrahydro-azeto[2,1-a]isoquinolin-2-one     (312 mg, 0.751 mmol) in dioxane (10 ml) and 6 M aq. HCl (30 ml) is     stirred at 95° C. for 3 h. The solvent is removed under reduced     pressure and the resulting residue is dissolved water/ethanol. The     solution is neutralized with 2 M aq. NaOH and evaporated. The     residue is suspended in methanol and filtered. The filtrate is     evaporated and purified by MPL-chromatography on Rp-C₁₈ silica gel     to yield     (±)-(S*)-((1S*)-1-benzyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid (97 mg) as a colourless foam. ¹H-NMR (300 MHz, CDCl₃):     2.00–2.12 (m, 1H), 2.13–2.26 (m, 1H), 2.40–2.60 (m, 1H), 2.68–2.88     (m, 1H), 3.17 (d, J=13.4, 1H), 3.53 (d, J=13.4, 1H), 3.71 (s, 6H),     4.88 (s, 1H), 6.13 (s, 1H), 6.51 (s, 2H), 6.69 (d, J=7, 2H), 6.75     (d, J=7.5, 1H), 6.95 (d, J=7.5, 1H), 7.00–7.09 (m, 3H), 7.09–7.18     (m, 2H). LC-MS²: t_(R)=4.01 min, [M+1]⁺=434.24, [M−1]⁻=432.31.

Example 11

(±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid is prepared in analogy to the procedures given in Example 1 and 9. ¹H-NMR (300 MHz, CDCl₃): 2.50–2.64 (m, 1H), 2.70–2.90 (m, 2H), 2.96–3.10 (m, 1H), 3.71 (s, 6H), 3.85 (s, 3H), 3.87 (s, 3H), 5.08 (s, 1H), 6.11 (s, 1H), 6.38 (s, 2H), 6.79 (s, 1H), 7.22–7.32 (m, 2H), 7.40–7.50 (m, 3H). LC-MS²: t_(R)=3.80 min, [M+1]⁺=480.36, [M−1]⁻=478.47.

Example 12

(±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (205 mg, 0.43 mmol) is acetylated in analogy to the procedure given in Example 5 to furnish (±)-(S*)-((1S*)-2-acetyl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-(3,5-dimethoxy-phenoxy)-acetic acid (92 mg). LC-MS²: t_(R)=4.40 min, [M+1]⁺=522.37, [M−1]⁻=520.32.

Example 13

(±)-(S*)-((1S*)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid is prepared starting from 6,7-dimethoxy-1-phenyl-3,4-dihydro-isoquinoline in analogy to the procedures given in Example 8. ¹H-NMR (300 MHz, CDCl₃): 2.72–2.87 (m, 1H), 3.10–3.40 (m, 3H), 3.61 (s, 3H), 3.75 (s, 6H), 3.81 (s, 3H), 5.57 (s, 1H), 6.06 (s, 1H), 6.53 (s, 1H), 6.60 (s, 1H), 7.18–7.24 (m, 3H), 7.56–7.62 (m, 2H). LC-MS²: t_(R)=3.61 min, [M+1]⁺=482.43, [M−1]⁻=480.55.

Example 14

-   a)     (±)-(1S*,9bS*)-1-Phenoxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     is prepared, starting from 1-phenyl-4,5-dihydro-3H-benzo[c]azepine     (Example 15) and phenoxy-acetic acid, according to procedure     described in Example 15. ¹H-NMR (300 MHz, CDCl₃): 1.59–1.81 (m, 2H),     2.45 (dd, J=11.7, 14.5, 1H), 2.66 (dd, J=7.3, 14.8, 1H), 3.10 (dt,     J_(d)=3.8, J_(t)=12.8, 1H), 4.09 (dt, J_(d)=13.6, J_(t)=3.6, 1H),     5.72 (s, 1H), 6.73–7.27 (m, 14H). LC-MS²: t_(R)=5.51 min,     [M+1]⁺=356.23, [M−1]⁻=354.17. -   b) A solution of     (±)-(1S*,9bS*)-1-phenoxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (480 mg, 1.35 mmol) in dioxane (8 ml) and 6 M aq. HCl (7 ml) is     stirred for 2 h at 75° C. and for 1 h at 90° C. 37% aq. HCl (1 ml)     is added and the mixture is stirred for 30 h at 90° C. and for 64 h     at rt. The organic solvent is evaporated in vacuo and the remaining     solution acidified to pH 6. The residue is purified by preparative     HPLC to give     (±)-(1S*,1′S*)-phenoxy-(1′-phenyl-2′,3′,4′,5′-tetrahydro-1H-benzo[c]azepin-1′-yl)-acetic     acid (140 mg) as a white powder. LC-MS¹: t_(R)=0.79 min,     [M+1]⁺=374.06.

Example 15

-   a) To a solution of 3-phenylpropylamine (10.6 ml, 74.0 mmol) in dry     DCM (100 ml) and triethylamine (10.3 ml, 74.0 mmol) is added     benzoylchloride (8.6 ml, 74.0 mmol) at 0° C. The suspension is     stirred at rt for 16 h. The mixture is poured into water and     extracted twice with EA. The organic phase is washed once with 2 M     aq. HCl, once with sat. aq. NaHCO₃, and once with sat aq. NaCl. The     organic phase is dried over Na₂SO₄ and evaporated to give     N-(3-phenyl-propyl)-benzamide (17.8 g) as a light yellow oil.     LC-MS²: t_(R)=4.56 min, [M+1]⁺=240.12. -   b) 1-Phenyl-4,5-dihydro-3H-benzo[c]azepine is prepared from     N-(3-phenyl-propyl)-benzamide, in analogy to procedures given     by N. H. Martin, C. W. Jefford in Helv. Chim. Acta, 75, (1982),     762–774. LC-MS²: t_(R)=2.95 min, [M+1]⁺=222.09. -   c) To a solution of 1-phenyl-4,5-dihydro-3H-benzo[c]azepine (440 mg,     1.99 mmol) and (3,5-dimethoxy-phenoxy)-acetic acid (507 mg, 2.39     mmol) in dry DCM (15 ml) and triethylamine (1.1 ml, 7.96 mmol) is     added of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (760 mg, 2.99     mmol) at 0° C. The suspension is stirred for 3 h at rt. The mixture     is poured into DCM and the organic phase is washed once with sat.     aq. NaHCO₃ and once with sat. aq. NaCl. The organic phase is dried     over Na₂SO₄ and evaporated. The crude product is purified by column     chromatography (silicagel, heptane:EA from 2:1 to 1:1) to give of     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]-cyclobuta[c]cyclohepten-2-one     (250 mg) as a brown solid. LC-MS²: t_(R)=5.51 min, [M+1]⁺=416.32. -   d) A solution of     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (250 mg, 602 μmol) in 2.4 M HCl in dioxane (7 ml) and water (20 μl)     is stirred for 2 h at 55° C. After stepwise addition of 37% aq. HCl     (2.75 ml) and stepwise heating to 75° C. for a total of 115 h the     organic solvent is evaporated in vacuo. The remaining solution is     acidified to pH 6 and the formed precipitate is filtered off. The     brown solid is purified by preparative HPLC to give     (±)-(1S*,1′S)-(3,5-dimethoxy-phenoxy)-(1′-phenyl-2′,3′,4′,5′-tetrahydro-1H-benzo[c]azepin-1′-yl)-acetic     acid (60 mg) as a red-brown solid. LC-MS²: t_(R)=4.03 min,     [M+1]⁺=434.34, [M−1]⁻=432.23.

Example 16

A solution of (±)-(1S*,1′S*)-(3,5-dimethoxy-phenoxy)-(1′-phenyl-2′,3′,4′, 5′-tetrahydro-1H-benzo[c]azepin-1′-yl)-acetic acid (34 mg, 78 μmol, Example 15), N-ethyldiisopropylamine (67 μl, 390 μmol) and chlorotrimethylsilane (12 μl, 94 μmol) in dry THF (4 ml) is stirred for 2 h at 55° C. The cloudy solution is cooled to rt and acetyl chloride (8.3 μl, 117 μmol) is added. The solution is stirred for 2 h at rt. The mixture is poured into 0.1 M aq. HCl. The aqueous phase is extracted twice with DCM. The organic phase is dried over Na₂SO₄ and evaporated. The crude product is purified by preparative HPLC to give (±)-(1S*,1′S*)-(2′-acetyl-1′-phenyl-2′,3′,4′,5′-tetrahydro-1H-benzo[c]azepin-1′-yl)-(3,5-dimethoxy-phenoxy)-acetic acid (5 mg) as a white powder. LC-MS¹: t_(R)=0.96 min, [M+1]⁺=476.17.

Example 17

-   a) A suspension of (3,5-dimethoxyphenyl)acetic acid (75 mg, 383     μmol) in dry toluene (5 ml) and thionyl chloride (111 μl, 1.53 mmol)     is stirred at 85° C. for 2 h and the solvent is evaporated to give     crude (3,5-dimethoxy-phenoxy)-acetyl chloride as a slightly brown     solid. -   b) A solution of     (±)-(1S*,1′S*)-1-(3,5-dimethoxy-phenoxy)-(1′-phenyl-2′,3′,4′,5′-tetrahydro-1H-benzo[c]azepin-1′-yl)-acetic     acid (34 mg, 78 μmol, Example 15), N-ethyldiisopropylamine (67 μl,     390 μmol) and chlorotrimethylsilane (12 μl, 94 μmol) in dry THF     (4 ml) is stirred for 2 h at 55° C. The cloudy solution is cooled to     rt and half of the crude (3,5-dimethoxy-phenoxy)-acetyl chloride,     dissolved in dry THF (1 ml), is added. The solution is stirred for 2     h at rt. The mixture is poured into 0.1 M aq. HCl. The aqueous phase     is extracted twice with DCM, the organic phase dried over Na₂SO₄ and     evaporated. The crude product is purified by preparative HPLC to     give     (±)-(1S*,1′S*)-(3,5-dimethoxy-phenoxy)-{2′-[2-(3,5dimethoxy-phenyl)-acetyl]-1′-phenyl-2′,3′,4′,5′-tetrahydro-1H-benzo[c]azepin-1′-yl}-acetic     acid (4.3 mg) as a white powder. LC-MS¹: t_(R)=1.06 min,     [M+1]⁺=612.20.

Example 18

-   a) Benzyl alcohol (16.4 ml, 158 mmol), dissolved in dry THF (100     ml), is added to a suspension of NaH (60% in mineral oil) (13.2 g,     330 mmol) in dry THF (300 ml) at 0° C. The mixture is stirred for 30     min at 0° C., for 30 min at 45° C., then for 1 h at rt. Bromo-acetic     acid (20 g, 144 mmol), dissolved in dry THF (100 ml), is added to     the mixture. The suspension is stirred for 6 h at 65° C., then for     16 h at rt. The mixture is poured into water and extracted twice     with EA. The aqueous phase is acidified, extracted twice with EA,     which is dried over MgSO₄ and evaporated. Benzyloxy-acetic acid (18     g ) is obtained as a light yellow oil. LC-MS²: t_(R)=3.17 min,     [M+1]⁺=165.02. -   b) To a solution of 1-phenyl-4,5-dihydro-3H-benzo[c]azepine (1.16 g     5.24 mmol, Example 15), benzyloxy acetic acid (1.3 g, 7.86 mmol) and     triethylamine (3.65 ml, 26.2 mmol) in DCM (30 ml) is added     bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.67 g, 10.5 mmol) in     two portions at 0° C. The mixture is allowed to come to rt and is     stirred overnight before it is diluted with DCM and washed with sat.     aq. NaHCO₃ and brine. The aq. phase is extracted again with DMC. The     combined organic phase is dried over MgSO₄ and evaporated. The crude     product is purified by column chromatography on silica gel eluting     with DCM containing 0–10% of methanol to give     (±)-(1S*,9bS*)-1-benzyloxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (124 mg) as a yellow solid. ¹H-NMR (300 MHz, CDCl₃): 1.56–1.76 (m,     1H), 1.76–1.92 (m, 1H), 2.44–2.56 (m, 1H), 2.66–2.80 (m, 1H),     3.08–3.26 (m, 1H), 4.12–4.25 (m, 1H), 4.36 (d, J=10.8, 1H), 4.52 (d,     J=10.8, 1H), 5.21 (s, 1H), 6.90–7.04 (m, 3H), 7.09–7.51 (m, 11H).     LC-MS¹: t^(R)=1.11 min, [M+1]⁺=370.10. -   c) A mixture of     (±)-(1S*,9bS*)-1-benzyloxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (124 mg, 0.338 mmol) and Pd/C (104 mg, 10% Pd) in THF (6 ml),     ethanol (6 ml) and acetic acid (0.2 ml) is stirred at 40° C. under 6     atm H₂ overnight. A second portion of Pd/C (104 mg) is added and     stirring under 6 atm H₂ at 50° C. is continued for another 2 h. The     mixture is filtered and the filtrate is evaporated to furnish     (±)-(1S*,9bS*)-1-hydroxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]-cyclobuta[c]cyclohepten-2-one     (92 mg) as a white powder. LC-MS¹: t_(R)=0.94 min, [M−1]⁻=280.10,     LC-MS²: t_(R)32 4.17 min, [M+1]⁺=280.13. -   d)     (±)-(1S*,9bS*)-1-Hydroxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]-cyclobuta[c]cyclohepten-2-one     (45 mg, 0.161 mmol) is added to a suspension of NaH (8.5 mg 60% in     mineral oil, 0.209 mmol) in THF (2 ml). The mixture is strirred at     rt for 1 h before 4,6-dimethoxy-2-methysulfanyl-pyrimidine (45 mg,     0.209 mmol, Example 8) is added. Stirring is continued for 16 h. The     mixture is partitioned between EA and sat. aq. NaHCO₃, the organic     phase is washed with sat. aq. NaHCO₃ and brine, the aq. phase is     extracted once more with EA. The combined organic phase is dried     over MgSO₄ and evaporated. The crude product is purified by     chromatography on prep. tlc plates with heptane:EA 3:7 to furnish     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (41 mg) as a solid. LC-MS¹: t_(R)=1.19 min, [M+1]⁺=418.13. -   e) At rt, a solution of LiOH.H₂O (8.2 mg, 0.2 mmol) in water     (0.25 ml) is added to a solution of     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (41 mg, 0.1 mmol) in THF (0.5 ml) and methanol (0.25 ml). The     resulting solution is stirred for 3 h before additional LiOH.H₂O (12     mg, 0.3 mmol) in water (0.1 ml) is added. After 4 h another portion     of LiOH.H₂O (25 mg, 0.6 mmol) in water (0.1 ml) is added. Stirring     is continued at rt for 16 h, then at 50° C. for 4 h. The reaction     mixture is neutralized by adding 1N aq. HCl, and lyophilized. The     crude product is purified by HPLC on Rp-C₁₈ silica gel to give     (±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-((1S*)-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)-acetic     acid (40 mg) as a white lyophilisate. LC-MS¹: t_(R)=0.85 min,     [M+1]⁺=436.14.

Example 19

-   a) 2-Methanesulfonyl-4,6-dimethyl-pyrimidine is prepared by     alkylation of 4,6-dimethyl-2-mercaptopyrimidine with methyliodide in     aq. NaOH followed by the oxidation of the obtained     4,6-dimethyl-2-methylsulfanyl-pyrimidine with peracetic adic in DCM.     ¹H-NMR (300 MHz, CDCl₃): 2.62 (s, 6H), 3.35 (s, 3H), 7.22 (s, 1H).     LC-MS¹: t_(R)=0.72 min, [M+1]⁺=187.07. -   b)     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (61 mg) is prepared starting from     (±)-(1S*,9bS*)-1-hydroxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]-cyclobuta[c]cyclohepten-2-one     (45 mg, 0.161 mmol, Example 18) and     2-methanesulfonyl-4,6-dimethyl-pyrimidine (39 mg, 0.209 mmol) as     described in Example 18. LC-MS¹: t_(R)=1.13 min, [M+1]⁺=386.13. -   c)     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((1S*)-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)-acetic     acid (30 mg) is obtained as a white powder by reacting     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]-cyclohepten-2-one     (61 mg, 0.38 mmol) with LiOH.H₂O as described in Example 18. LC-MS¹:     t_(R)=0.82 min, [M+1]⁺=404.13.

Example 20

-   a) 8-Chloro-1-phenyl-4,5-dihydro-3H-benzo[c]azepine is prepared in     analogy to Example 15. LC-MS¹: t_(R)=0.80 min, [M+1]⁺=256.02. -   b)     (±)-(1S*,9bS*)-1-Benzyloxy-8-chloro-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     is obtained starting from     8-chloro-1-phenyl-4,5-dihydro-3H-benzo[c]azepine following the     procedure given in Example 15. LC-MS¹: t_(R)=1.28 min,     [M+1]⁺=404.02. -   c) Hydrogenation of     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     in THF/ethanol in the presence of 5% 4M HCl in dioxane gives     (±)-(1S*,9bS*)-1-hydroxy-8-chloro-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one.     ¹H-NMR (300 MHz, D₆ ⁻DMSO): 1.36–1.54 (m, 1H), 1.73–1.86 (m, 1H),     2.27 (dd, J=11.7, 14.0, 1H), 2.75 (dd, J=7.9, 15.0 , 1H), 3.03 (dt,     J_(d)=3.7, J_(t)=13.6, 1H), 3.93 (dt, J_(d)=13.6, J_(t)=3.3, 1H),     5.24 (d, J=6.4, 1H), 6.24 (d, J=6.4, 1H), 6.86–6.95 (m, 2H),     7.22–7.43 (m, 5H), 7.55 (d, J=2.2, 1H). LC-MS¹: t_(R)=0.92 min,     [M+1]⁺=313.98. -   d) Reaction of     (±)-(1S*,9bS*)-1-hydroxy-8-chloro-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     with 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8) followed     by β-lactam hydrolysis as described in Example 18 yields     (±)-(S*)-((1S*)-8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)-(4,6-di-methoxypyrimidin-2-yloxy)-acetic     acid as a white powder. LC-MS¹: t_(R)=0.90 min, [M+1]⁺=470.12.

Example 21

Following the procedures given in Example 18, (±)-(S*)-((1S*)-8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)-(4,6-dimethylpyrimi-din-2-yloxy)-acetic acid is obtained as a white powder starting from (±)-(1S*,9bS*)-1-hydroxy-8-chloro-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one (Example 20) and 2-methanesulfonyl-4,6-dimethyl-pyrimidine (Example 19). LC-MS¹: t_(R)=0.86 min, [M+1]⁺=438.12.

Example 22

-   a) 7-Chloro-5-phenyl-2,3-dihydro-benzo[f][1,4]oxazepine is prepared     according to procedures given by J. B. Bremner, E. J.     Browne, I. W. K. Gunawardana in Aust. J. Chem. 37 (1984), 129–141. -   b) To a solution of     7-chloro-5-phenyl-2,3-dihydro-benzo[f][1,4]oxazepine (2.0 g, 7.76     mmol) and benzyloxy-acetic acid (Example 5c) (1.93 g, 11.6 mmol) in     dry DCM (20 ml) and triethylamine (5.4 ml, 38.7 mmol)     bis(2-oxo-3-oxazolidinyl)phosphinic chloride (3.95 g, 15.5 mmol) is     added at 0° C. The suspension is stirred at 0° C. and is allowed to     slowly warm to rt. Stirring is continued for 18 h. The mixture is     poured into sat. aq. NaHCO₃ and extracted three times with DCM. The     organic phase is dried over MgSO₄ and evaporated. The crude product     is purified by column chromatography (silica gel, heptane:EA 1:1) to     give     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (3.04 g) as a white solid. LC-MS²: t_(R)=5.39 min, [M+1]⁺=406.15;     ¹H-NMR (300 MHz, CDCl₃): 3.38 (ddd, J=3.3, 9.3, 13.7, 1H), 3.78     (ddd, J=2.7, 9.5, 12.3, 1H), 4.08 (ddd, J=2.6, 3.5, 13.7, 1H), 4.20     (dt, J_(d)=12.3, J_(t)=3.5, 1H), 4.37 (d, J=11.2, 1H), 4.49 (d,     J=11.2, 1H), 5.05 (d, 1H), 6.97–7.04 (m, 4H), 7.13–7.17 (m, 2H),     7.24–7.28 (m, 4H), 7.35–7.40 (m, 3H). -   c) To a solution of     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (1.0 g, 2.46 mmol) in ethanol (30 ml) and 1,2-dichlorobenzene (6     ml), a suspension of 10% Pd on charcoal (100 mg) in ethanol (1 ml)     is added. The mixture is stirred for 70 min under an atmosphere of     hydrogen gas (balloon). The catalyst is filtered and the filtrate is     evaporated in vacuo. The remaining residue is suspended in diethyl     ether, the solid material is collected, washed with diethyl ether     and dried to give     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (707 mg) as an off-white powder. LC-MS²: t_(R)=4.10 min,     [M+1]⁺=316.05, [M−1]⁻=313.81. -   d) To a suspension of NaH (60% in mineral oil) (52 mg, 1.30 mmol) in     dry THF (6 ml) and dry DMF (2 ml)     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (250 mg, 792 μmol) is added. The mixture is stirred for 5 min at rt     before 2-methanesulfonyl-4,6-dimethyl-pyrimidine (Example 19) (221     mg, 1.19 mmol) is added. The mixture is stirred at rt for 3 h,     diluted with EA and washed with sat. aq. NaHCO₃ and twice with     water. The organic layer is dried over MgSO₄. The product slowly     crystallises upon evaporation of the solvent. The solid material is     collected, washed with diethyl ether and dried to give     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (269 mg) as white crystals. LC-MS²: t_(R)=4.99 min, [M+1]⁺=422.17. -   e) A solution of     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (200 mg, 474 μmol) in THF (3 ml), methanol (2 ml) and 2 N aq.     lithium hydroxyde (2 ml) is stirred at 60° C. for 5 h. The pH is     adjusted to 5 by the addition of 10% aq. acetic acid (approx.     2.5 ml) and the resulting mixture is extracted three times with DCM.     The organic phase is dried over Na₂SO₄ and evaporated. The crude     product is purified on prep. tlc plates (DCM containing 10% of     methanol) to give     (±)-(1S*,5′S*)-(7′-chloro-5′-phenyl-2′,3′,4′,5′-tetrahydro-benzo[f][1,4]oxazepin-5′-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid (143 mg) as a colourless foam. LC-MS²: t_(R)=3.63 min,     [M+1]⁺=440.21, [M−1]⁻=438.08.

Example 23

-   a) To a suspension of NaH (60% in mineral oil) (52 mg, 1.3 mmol) in     dry THF (6 ml) and dry DMF (2 ml)     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (Example 22) (250 mg, 792 μmol) is added. The mixture is stirred for     5 min at rt and 2-methanesulfonyl-4,6-dimethoxy-pyrimidine     (Example 8) (260 mg, 1.19 mmol) is added. Stirring is continued for     3 h before the mixture is diluted with EA and washed with sat. aq.     NaHCO₃ and twice with water. The organic layer is dried over MgSO₄     and evaporated. The product is crystallised from diethyl ether to     give     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cy-clohepten-2-one     (329 mg) as white crystals. LC-MS²: t_(R)=5.30 min, [M+1]⁺=454.20. -   b) A solution of     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cy-clohepten-2-one     (200 mg, 441 μmol) in THF (4 ml), methanol (3 ml) and 2 N aq.     lithium hydroxyde (2 ml) is stirred at 50° C. for 6 h. The organic     solvents are removed and the aqueous solution is diluted with water     and acidified with 10% aq. acetic acid (approx. 3 ml). The mixture     is extracted three times with DCM. The organic phase is evaporated     and the crude product is purified on prep. tlc-plates     (DCM:methanol:water:acetic acid 100:20:2:1) to give     (±)-(1S*,5′S*)-(7′-chloro-5′-phenyl-2′,3′,4′,5′-tetrahydro-benzo[f][1,4]oxazepin-5′-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid (96 mg) as a white powder. LC-MS²: t_(R)=3.88 min,     [M+1]⁺=472.26, [M−1]⁻=470.06.

Example 24

-   a) To a suspension of 10% Pd on charcoal (200 mg) in ethanol (10 ml)     a solution of     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (360 mg, 887 μmol, Example 22) in THF:ethanol 1:1 (15 ml), followed     by acetic acid (approx. 0.5 ml), is added. The mixture is stirred at     rt under an atmosphere of 7 atm hydrogen gas for 2.5 h. The catalyst     is filtered off and the filtrate is evaporated. The crude product is     purified by column chromatography (silica gel, EA) to give     (±)-(1S*,9bS*)-1-hydroxy-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclo-hepten-2-one     (235 mg) as a white crystaline solid. LC-MS²: t_(R)=3.72 min,     [M+1]⁺=282.10, [M−H]⁻=280.00. -   b) To a solution of     (±)-(1S*,9bS*)-1-hydroxy-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (227 mg, 807 μmol) in dry THF (6 ml) and dry DMF (2 ml) NaH (60% in     mineral oil) (46 mg, 1,15 mmol) is added. The mixture is stirred at     rt for 5 min and 2-methanesulfonyl-4,6-dimethyl-pyrimidine (195 mg,     1.05 mmol, Example 19) is added. The resulting mixture is stirred at     rt for 2 h before it is diluted with EA and washed with sat. aq.     NaHCO₃ followed by water. The organic phase is evaporated. The     product crystallises, the obtained crystals are collected, washed     with diethyl ether and dried to furnish     (±)-(1S*,9bS*)-(1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (196 mg) as white crystals. LC-MS²: t_(R)=4.66 min, [M+1]⁺=388.19. -   c) A solution of     (±)-(1S*,9bS*)-(1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-1,3,4,9b-tetrahydro-5-oxa-2a-aza-benzo[a]cyclobuta[c]cyclohepten-2-one     (100 mg, 258 μmol) and lithium hydroxyde monohydrate (18 mg, 429     μmol) in THF (5 ml), methanol (5 ml) and water (2 ml) is stirred at     55° C. for 18 h, at 65° C. for 144 h before further lithium     hydroxyde monohydrate (30 mg, 715 μmol) is added. Stirring of the     solution is continued for 24 h at 65° C. The pH is adjusted to 5 by     adding acetic acid. The solvent is removed and the crude product is     purified by preparative HPLC. Product fractions are lyophilised to     give     (±)-(1S*,5′S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-(5′-phenyl-2′,3′,4′,5′-tetrahydro-benzo[f][1,4]oxazepin-5′-yl)-acetic     acid (58 mg) as a white lyophilisate. LC-MS²: t_(R)=3.38 min,     [M+1]⁺⁼406.10, [M−1]⁻=404.09.

Example 25

-   a) 5-Phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine is prepared     starting from 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 27) as described in the literature (L. H. Sternbach, E.     Reeder, G. A. Archer, J. Org. Chem. 28 (1963), 2456–2459). ¹H-NMR     (300 MHz, CDCl₃): 3.82–3.88 (m, 2H), 3.96–4.02 (m, 3H), 6.66–6.74     (m, 2H), 6.99–7.05 (m, 1H), 7.15–7.24 (m, 1H), 7.32–7.42 (m, 3H),     7.51–7.56 (m, 2H). LC-MS¹: t_(R)=0.76 min, [M+1]⁺=223.05. -   b) Benzoylchloride (0.64 ml, 5.5 mmol) is slowly added at 10° C. to     a solution of 5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine (1.11     g, 5 mmol) and triethylamine (1.05 ml, 7.5 mmol) in DCM (25 ml). The     mixture is stirred for 2 h at rt, diluted with EA and washed with     water. The aq. phase is extracted once more with EA, the organic     phase is washed with brine. The combined organic phase is dried over     MgSO₄ and evaporated. The residue is suspended in boiling diethyl     ether. The solid material is collected, washed with additional     diethyl ether and dried to give     phenyl-(5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-methanone     (0.7 g) as beige crystals. LC-MS¹: t_(R)=0.69 min, [M+1]⁺=327.03. -   c) Benzyloxyacetyl chloride (0.45 ml, 2.74 mmol) is slowly added at     0° C. to a solution of     phenyl-(5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-methanone     (0.69 g, 2.11 mmol) and triethylamine (0.88 ml, 6.33 mmol) in DCM     (15 ml). The mixture is allowed to come to rt and is stirred for 16     h before it is diluted with EA, washed with sat. aq. NaHCO₃, water     and brine. The aq. phase is extracted once more with EA. The     combined organic phase is dried over MgSO₄ and evaporated. The     product is crystallised from EA/diethyl ether to furnish     (±)-(1S*,9bS*)-5-benzoyl-1-benzyloxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-2-one     (0.9 g) as a white powder. LC-MS¹: t_(R)=1.13 min, [M+1]⁺=475.05 -   d) A solution of     (±)-(1S*,9bS*)-5-benzoyl-1-benzyloxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-2-one     (1.6 g, 3.35 mmol) in THF (45 ml), ethanol (15 ml) and acetic acid     (0.5 ml) is treated with a suspension of Pd/C (0.5 g, 10% Pd) in THF     (3 ml). The mixture is stirred at 45° C. under 7 atm of H₂ for 22 h.     The catalyst is filtered off and the filtrate is evaporated. The     residue is suspended in diethyl ether, filtered off, washed with     diethyl ether and dried to yield     (±)-(1S*,9bS*)-5-benzoyl-1-hydroxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (1.23 g) as white crystals. LC-MS¹: t_(R)=0.89 min, [M+1]⁺=384.96. -   e) A mixture of K₂CO₃ (1.25 g, 9 mmol),     (±)-(1S*,9bS*)-5-benzoy-1-hydroxy-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (1.15 g, 3 mmol), and 2-methanesulfonyl-4,6-dimethyl-pyrimidine     (0.67 g, 3.6 mmol, Example 19) in DMF (30 ml) is stirred at 40° C.     for 58 h before it is diluted with EA and washed three times with     water. The aq. phase is extracted once more with EA. The combined     organic phase is dried over MgSO₄ and evaporated and dried to give     crude     (±)-(1S*,9bS*)-5-benzoyl-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (1.5 g) as a white powder. LC-MS¹: t_(R)=1.05 min, [M+1]⁺=491.00. -   f) A 2 N solution LiOH.H₂O (2 ml) is added to a solution of crude     (±)-(1S*,9bS*)-5-benzoyl-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (491 mg, 1 mmol) in THF (8 ml) and methanol (4 ml). The resulting     solution is stirred at rt for 40 h before it is diluted with 10% aq.     citric acid and extracted three times with DCM. The organic phase is     washed with water, dried over MgSO₄ and evaporated. The crude     product is purified on prep. tlc plates with DCM:methanol 9:1 to     furnish     (±)-(S*)-((5S*)-1-benzoyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid (130 mg) as a white powder. LC-MS¹: t_(R)=0.95 min,     [M+1]⁺=509.02.

Example 26

-   a) NaH is added (1.3 g, 55% in mineral oil, 29.7 mmol) in portions     to an ice-cold solution of     5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine (6.0 g, 27 mmol,     Example 25) in DMF (75 ml). The mixture is stirred at rt for 15 min     before a solution of 4-methoxybenzyl chloride (4.53 ml, 32.4 mmol)     in DMF (5 ml) is added. The orange suspension is stirred at rt for 8     h, diluted with EA and washed with cold water. The aq. phase is     extracted two more times with EA. The organic phase is washed with     brine, dried over MgSO₄ and evaporated. The crude product is     purified by column chromatography on silica gel eluting with     DCM:methanol 30:1 to 20:1 to furnish     1-(4-methoxy-benzyl)-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine     (8.0 g) as an orange solid. LC-MS¹: t_(R)=0.86 min, [M+1]⁺=343.07. -   b) Starting from     1-(4-methoxy-benzyl)-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine     (27.31 g, 76.62 mmol), the [2+2]-cycloaddition and the hydrogenation     is performed as described in Example 25 to give     (±)-(1S*,9bS*)-1-hydroxy-5-(4-methoxy-benzyl)-9b-phenyl-3,4,5,9b-tetra-hydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (28.87 g) as a white powder. ¹H-NMR (300 MHz, CDCl₃): 3.30 (d, J=15,     1H), 3.78 (s, 3H), 3.86 (d, J=13.5, 1H), 4.50 (d, J=13.5, 1H). 4.53     (d, J=15, 1H), 5.40 (s, 1H), 6.68–6.75 (m, 2H), 7.00–7.04 (m, 2H),     7.28–7.46 (m, 7H), 7.64–7.70 (m, 1H). LC-MS¹: t_(R)=0.96 min,     [M+1]⁺=415.04. -   c) The introduction of the 4,6-dimethylpyrimidine and the β-lactam     cleavage are carried out as described in Example 25 to yield     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid as a white powder. LC-MS¹: t_(R)=0.95 min, [M+1]⁺=525.06.

Example 27

-   a) 5-Phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one is prepared     starting from 2-aminobenzophenone and bromo-acetyl bromide in     analogy to procedures given by M. G. Bock, R. M. DiPardo, B. E.     Evans, K. E. Rittle, D. F. Veber, R. M. Freidinger, J.     Hirshfield, J. P. Springer, J. Org. Chem., 52, (1987), 3232–3239.     LC-MS²: t_(R)=3.09 min, [M+1]⁺=237.00. -   b) (6-Phenyl-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl)-acetic acid     ethyl ester is prepared starting from     5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one and ethyl     3-hydrazino-3-oxopropionate following the procedures described by A.     Walser, T. Flynn, C. Mason, H. Crowley, C. Maresca, B. Yaremko, M.     O'Donnell, J. Med. Chem. 34 (1991), 1209–1221. ¹H-NMR (300 MHz,     CDCl₃): 1.18 (t, J=7.1, 3H), 4.04–4.17 (m, 5H), 5.49 (d, J=12.8,     1H), 7.31–7.48 (m, 5H), 7.51–7.70 (m, 4H). LC-MS²: t_(R)=3.91 min,     [M+1]⁺=347.18, [M−1]⁻=344.81. -   c) At 0° C. benzyloxyacetyl chloride (616 mg, 3.33 mmol) is added to     a solution of     (6-phenyl-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl)-acetic acid     ethyl ester (770 mg, 2.22 mmol), trethylamine (1.55 ml, 11.11 mmol)     in DCM (20 ml). The mixture is stirred at 0° C. for 40 min, then at     rt for 20 h before it is diluted with EA and washed three times with     sat. aq. NaHCO₃. The aq. phase is extracted with EA. The combinded     organic phase is dried over MgSO₄ and evaporated. The resulting     solid is supsended in diethyl ether, filtered, washed with     additional diethyl ether and dried to furnish     (±)-((1S*,10bS*)-1-benzyloxy-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulen-6-yl)-acetic     acid ethyl ester (863 mg) as a beige powder. LC-MS²: t_(R)=4.53 min,     [M+1]⁺=495.28, [M−1]⁻=493.17. -   d) A suspension of Pd/C (500 mg, 10% Pd) in THF is added to a     solution of     (±)-((1S*,10bS*)-1-benzyloxy-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulen-6-yl)-acetic     acid ethyl ester (860 mg, 1.74 mmol) in THF (25 ml), ethanol (10 ml)     and acetic acid (2 ml). The mixture is stirred at 50° C. under 7 atm     H₂ for 57 h. The Pd-catalyst is filtered off and the filtrate is     evaporated. The residue is dissolved in DCM (10 ml), diluted with EA     (250 ml) and washed twice with sat. aq. NaHCO₃, once with water. The     organic phase is dried over MgSO₄ and evaporated to give     (±)-((1S*,10bS*)-1-hydroxy-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a     ,4,5,6a-tetraaza-benzo[h]cyclobuta[f]-azulen-6-yl)-acetic acid ethyl     ester (491 mg) as a beige powder. ¹HNMR-(300 MHz, CDCl₃): 1.24 (t,     J=7.1, 3H), 2.97 (d, J=16.8, 1H), 3.41 (d, J=17.0, 1H), 4.16 (q,     J=7.1, 2H), 4.33 (d, J=14.6, 1H), 5.35 (d, J=14.8, 1H), 5.49(s, 1H),     6.90 (s br, 3H), 7.14–7.21 (m, 3H), 7.52 (d, J=7.7, 1H), 7.61 (t,     J=7.7, 1H), 7.70 (t, J=7.5, 1H), 7.90 (d, J=7.7, 1H). LC-MS²:     t_(R)=3.35 min, [M+1]⁺=405.35, [M−1]⁻=403.21. -   e) At 50° C., K₂CO₃ (341 mg, 2.47 mmol) followed by     2-methanesulfonyl-4,6-dimethyl-pyrimidine (184 mg, 0.989 mmol,     Example 19) is added to a solution of     (±)-((1S*,8aS*)-1-hydroxy-2-oxo-8a-phenyl-1,8a-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]-azulen-6-yl)-acetic     acid ethyl ester (200 mg, 0.495 mmol) in acetone (5 ml). The mixture     is stirred for 5 h, diluted with EA (75 ml) and washed twice with     water. The organic phase is evaporated and the crude product is     purified by column chromatography on silica gel eluting with DMC     containing 6% of methanol to furnish     (±)-((1S*,10bS*)-1-(4,6-dimethylpyrimidin-2-yloxy)-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]-azulen-6-yl)-acetic     acid ethyl ester (205 mg) as a colourless foam. LC-MS²: t_(R)=4.13     min, [M+1]⁺=511.34, [M−1]⁻=509.06. -   f) A 2 N aq. LiOH solution (2 ml) is added to a solution of     (±)-((1S*,     10bS*)-1-(4,6-dimethylpyrimidin-2-yloxy)-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]-azulen-6-yl)-acetic     acid ethyl ester in THF (6 ml) and methanol (5 ml) and the mixture     is stirred for 1 h at 50° C. before it is neutralised with acetic     acid (0.24 ml). The organic solvents are evaporated under reduced     pressure and the product is desalted over Rp-C₁₈ silica gel. The     product fractions are lyophilized to give     (±)-(S*)-((6S*)-1-carboxymethyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid (195 mg) as an off-white powder. LC-MS²: t_(R)=3.12 min,     [M+1]⁺=501.41, [M−1]⁻=499.47.

Example 28

(±)-(S*)-((6S*)-1-carboxymethyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 27 by reacting (±)-((1S*,10bS*)-1-hydroxy-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a ,4,5,6a-tetraaza-benzo[h]cyclobuta[f]-azulen-6-yl)-acetic acid ethyl ester with 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8), and subsequent cleaving of the ester and lactam functionality. LC-MS²: t_(R)=3.35 min, [M+1]⁺=533.39, [M−1]⁻=531.33.

Example 29

-   a) 37% aq. HCl (65 ml) is added dropwise to a suspension of     heptane-3,5-dione (36.35 g, 0.284 mol) and thiourea (18 g, 0.236     mol) in ethanol (500 ml). The resulting yellow solution is stirred     at 60° C. for 2 h, at 90° C. for 2 h and then at rt for 16 h. The     solvent is removed under reduced pressure and the residue is     suspended in boiling acetone. The solid material is collected,     washed with acetone and dried to give 4,6-diethyl-pyrimidine-2-thiol     (23 g) as yellow powder. The material is dissolved in 1 M aq. NaOH     (600 ml) and treated with methyliodide (30 ml, 0.478 mol). The     resulting emulsion is stirred at rt for 5 h before it is extracted     twice with EA. The organic phase is washed with brine, dried over     MgSO₄ and evaporated to give crude     4,6-diethyl-2-methylsulfanyl-pyrimidine (18.28 g) as a red oil.     Peracetic acid (37 ml, 39% in acetic acid, 0.22 mol) is slowly added     at 0° C. to a solution of the previously obtained oil in DCM (250     ml). The mixture is allowed to come to rt and is stirring is     continued for 16 h before it is washed three times with sat. aq.     NaHCO₃. The aq. phase is extracted once more with DCM. The combined     organic phase is dried over MgSO₄. The product crystallises upon     evaporation of the solvent. The solid material was dried under HV to     give 4,6-diethyl-2-methanesulfonyl-pyrimidine (20.09 g) as pale pink     crystals. ¹H-NMR (300 MHz, CDCl₃): 1.32 (t, J=7.5, 6H), 2.87 (q,     J=7.5, 4H), 3.34 (s, 3H), 7.22 (s, 1H). LC-MS¹: t_(R)=0.78 min,     [M+1]⁺=215.05. -   b)     (±)-(S*)-((6S*)-1-carboxymethyl-6-phenyl-5,6-dihydro4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-(4,6-diethyl-pyrimidin-2-yloxy)-acetic     acid is prepared in analogy to Example 27 by reacting     (±)-((1S*,10bS*)-1-hydroxy-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]-azulen-6-yl)-acetic     acid ethyl ester with 4,6-diethyl-2-methanesulfonyl-pyrimidine, and     cleaving of the ester and lactam functionality. LC-MS²: t_(R)=3.57     min, [M+1]⁺=529.32, [M−1]⁻=526.96.

Example 30

-   a) 8-Chloro-1-methyl-6-phenyl-4H-2,3,5,10b-tetraaza-benzo[e]azulene     is prepared following the procedure given in A. Walser, T. Flynn, C.     Mason, H. Crowley, C. Maresca, B. Yaremko, M O'Donnell, J. Med.     Chem. 34 (1991), 1209–1221. ¹H-NMR (300 MHz, CDCl₃): 2.64 (s, 3H),     4.08 (d, J=12.8, 1H), 5.49 (d, J=12.8, 1H), 7.36–7.55 (m, 7H), 7.65     (dd, J=2.6, 8.6, 1H). LC-MS¹: t_(R)=0.88 min, [M+1]⁺=309.07. -   b) 8-Chloro-1-methyl-6-phenyl-4H-2,3,5,10b-tetraaza-benzo[e]azulene     (500 mg, 1.62 mmol) is reacted with benzyloxyacetyl chloride as     described in Example 27 to give     (±)-(1S*,10bS*)-1-benzyloxy-9-chloro-6-methyl-10b-phenyl-1,10b-dihydro-3H-2a,4,5,6a-tetraaza-benzo[h]cyclo-buta[f]azulen-2-one     (397 mg) as a beige solid. LC-MS²: t_(R)=4.61 min, [M+1]⁺=457.26,     [M+HCOOH-1]⁻=500.99. -   c) Hydrogenation of     (±)-(1S*,10bS*)-1-benzyloxy-9-chloro-6-methyl-10b-phenyl-1,10b-dihydro-3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulen-2-one     (397 mg) following the procedure given in Example 27 gives     (±)-(1S*,10bS*)-1-hydroxy-6-methyl-10b-phenyl-1,10     b-dihydro-3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulen-2-one     (137 mg) as a beige solid. LC-MS²: t_(R)=2.92 min,     [M+1]⁺=333.25,[M−1]⁻=331.07. -   d) Reaction of     (±)-(1S*,10bS*)-1-hydroxy-6-methyl-10b-phenyl-1,10b-dihydro-3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulen-2-one     with 2-methanesulfonyl-4,6-dimethyl-pyrimidine and subsequent lactam     cleavage as described in Example 27 yields     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((6S*)-1-methyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic     acid. LC-MS²: t_(R)=3.29 min, [M+1]⁺=457.41, [M−1]⁻=454.99.     or: A solution of     (±)-(S*)-((6S*)-1-carboxymethyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid (40 mg, 0.08 mmol, Example 27) in DMF (3 ml) is stirred at     80° C. for 90 min. The solvent is removed under reduced pressure and     the remaining residue is suspended in diethyl ether. The solid     material is collected, washed with diethyl ether and dried to give     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((6S*)-1-methyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic     acid (34 mg) as a white powder. LC-MS²: t_(R)=3.29 min,     [M+1]⁺=457.46, [M−1]⁻=455.32.

Example 31

(±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-((6S*)-1-methyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid is obtained starting from (±)-(1S*, 10bS*)-1-hydroxy-6-methyl-10b-phenyl-1,10b-dihydro-3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulen-2-one (Example 30) and 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8) following the procedures given in Example 30. LC-MS²: t_(R)=3.44 min, [M+1]⁺=489.34, [M−1]⁻=487.46.

Example 32

-   a) Methyl hydrazidooxalate is prepared according to the procedure     given in the literature (J. Szmuszkovicz, M. E. Greig, J. Med.     Pharm. Chem. 4 (1961), 259–296). ¹H-NMR (300 MHz, D₆-DMSO): 3.74 (s,     3H), 4.59 (s br, 2H), 10.22 (s br,1H). ¹³C-NMR (75 MHz, D₆-DMSO):     53.4, 155.9, 161.4. -   b) 6-Phenyl-4H-2,3,5,10b-tetraaza-benzo[e]azulene-1-carboxylic acid     methyl ester is obtained as an off-white powder in analogy to the     procedure given in the literature (A. Walser, T. Flynn, C. Mason, H.     Crowley, C. Maresca, B. Yaremko, M O'Donnell, J. Med. Chem. 34     (1991), 1209–1221) starting from     5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (Example 27) and     methyl hydrazidooxalate. ¹H-NMR (300 MHz, CDCl₃): 4.01 (s, 3H), 4.07     (d, J=12.7, 1H), 5.55 (d, J=12.7, 1H), 7.34–7.65 (m, 9H). LC-MS²:     t_(R)=3.81 min, [M+1]⁺=319.22, [M−1]⁻=317.22. -   c) The [2+2]-cycloaddition, the hydrogenation, the introduction of     the 4,6-dimethylpyrimidine side chain are carried out as described     for Example 27 to give (±)-(1S*,     10bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-2-oxo-10b-phenyl-1,10b-dihydro-2H     ,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulene-6-carboxylic acid     methyl ester as a white solid. ¹H-NMR (300 MHz, CDCl₃): 2.31 (s,     6H), 3.75 (s, 3H), 4.39 (d, J=14.8, 1H), 5.41 (d, J=14.8, 1H), 6.56     (s, 1H), 6.59 (s, 1H), 6.75–7.12 (m, 5H), 7.35 (dd, J=1.3, 8.1, 1H),     7.62 (dt, J_(d)=1.4, J_(t)=7.7, 1H), 7.77 (dt, J_(d)=1.3, J_(t)=7.7,     1H), 8.87 (dd, J=1.3, 8.1, 1H). LC-MS²: t_(R)=4.02 min,     [M+1]⁺=483.54, [M−1]⁻=317.12 -   d) A 2 N aq. solution of LiOH.H₂O (1.5 ml) is added to a suspension     of     (±)-(1S*,10bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-2-oxo-10b-phenyl-1,10b-dihydro-2H     ,3H-2a ,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulene-6-carboxylic     acid methyl ester (220 mg, 0.456 mmol) in THF (7 ml) and methanol     (5 ml) and the resulting clear solution is stirred at 50° C. for     2 h. The solution is neutralised by adding acetic acid (0.24 ml) and     evaporated. The crude product is desalted over Rp-C₁₈ silica gel to     give     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((6S*)-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic     acid (205 mg) as a white powder. LC-MS²: t_(R)=3.30 min,     [M+1]⁺=443.25, [M−1]⁻=441.05.

Example 33

(±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-((6S*)-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid is obtained in analogy to Example 32 as a white powder starting from (±)-(1S*,10bS*)-1-hydroxy-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,4,5,6a-tetraaza-benzo[h]cyclobuta[f]azulene-6-carboxylic acid methyl ester and 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8). LC-MS²: t_(R)=3.49 min, [M+1]⁺=475.36, [M−1]⁻=473.21.

Example 34

-   a)     8-Chloro-1-methyl-6-phenyl-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic     acid ethyl ester is prepared starting from     2-amino-5-chloro-benzophenone following the procedures given in the     literature (R. I. Fryer, J. V. Earley, N. W. Gilman, W. Zally, J.     Heterocyclic Chem. 13 (1976), 433–437; A. Walser, T. Flynn, C.     Mason, R. I. Fryer, J. Heterocyclic Chem. 23 (1986), 1303–1314).     ¹H-NMR (300 MHz, D₆-DMSO): 1.29 (t, J=7.1, 3H), 2.49 (s, 3H), 3.96     (d, J=12.4, 1H), 4.21–4.30 (m, 2H), 5.69 (d, J=12.4, 1H), 7.33–7.55     (m, 6H), 7.81–7.86 (m, 2H). LC-MS¹: t_(R)=0.95 min, [M+1]⁺=380.05. -   b) The [2+2]-cycloaddition with     8-chloro-1-methyl-6-phenyl-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic     acid ethyl ester (1.02 g, 2.7 mmol) is carried out as described in     Example 27 to give     (±)-(1S*,10bS*)-1-benzyloxy-9-chloro-6-methyl-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,5,6a-triaza-benzo[h]cyclobuta[f]azulene-4-carboxylic     acid ethyl ester (1.1 g) as white crystals. LC-MS¹: t_(R)=1.07 min,     [M+1]⁺=528.14. -   c) The hydrogenation of     (±)-(1S*,10bS*)-1-benzyloxy-9-chloro-6-methyl-2-oxo-10b-phenyl-1,10b-dihydro-2H,3H-2a,5,6a-triaza-benzo[h]cyclobuta-[f]azulene4-carboxylic     acid ethyl ester is carried out at rt in analogy to Example 27 over     a period of 30 h. This yields     (±)-(1S*,10bS*)-1-hydroxy-6-methyl-2-oxo-10b-phenyl-1,10b-dihydro-2H     ,3H-2a,5,6a-triaza-benzo[h]cyclobuta[f]azulene-4-carboxylic acid     ethyl ester as a white powder. LC-MS¹: t_(R)=0.78 min,     [M+1]⁺=404.08. -   d) Introduction of the 4,6-dimethylpyrimidine, cleavage of the     β-lactam and the ethyl ester are carried out as described in     Example 27. The crude product is purified by prep. HPLC on Rp-C₁₈     silica gel to give     (±)-(6S*)-6-[(S*)-carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-1-methyl-6-phenyl-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic     acid as an off-white solid. LC-MS¹: t_(R)=0.69 min, [M+1]⁺=500.17.

Example 35

(±)-(6S*)-6-[(S*)-carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-1-methyl-6-phenyl-5,6dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid is prepared in analogy to Example 34. LC-MS¹: t_(R)=0.76 min, [M+1]⁺=532.18.

Example 36

-   a) The hydrogenation of     (±)-(1S*,10bS*)-1-benzyloxy-9-chloro-6-methyl-2-oxo-10b-phenyl-1,10b-dihydro-2H     ,3H-2a,5,6a-triaza-benzo[h]cyclobuta-[f]azulene4-carboxylic acid     ethyl ester (3.05 g, 5.76 mmol, Example 34) is carried out under 7     atm of H₂ at rt in THF (50 ml), ethanol (100 ml), 4 N HCl in dioxane     (10 ml) with Pd/C (2 g, 10% Pd) over a period of 1.5 h. This     furnishes     (±)-(1S*,10bS*)-9-chloro-1-hydroxy-6-methyl-2-oxo-10b-phenyl-1,10b-dihydro-2H     ,3H-2a ,5,6a-triaza-benzo[h]cyclobuta-[f]azulene-4-carboxylic acid     ethyl ester (1.8 g) as white crystals. LC-MS¹: t_(R)=0.84 min,     [M+1]⁺=438.08; LC-MS²: t_(R)=3.78 min, [M+1]⁺=438.22, [M−1]⁻=436.13. -   b) The introduction of the 4,6-dimethylpyrimidine and the ester and     β-lactam cleavage are performed as described in Example 34 to give     (±)-(6S*)-6-[(S*)-carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-8-chloro-1-methyl-6-phenyl-5,6-dihydro4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic     acid as a white powder. LC-MS¹: t_(R)=0.77 min, [M+1]⁺=534.12.

Example 37

(±)-(6S*)-6-[(S*)carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-8-chloro-1-methyl-6-phenyl-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid is prepared in analogy to Example 36. LC-MS¹: t_(R)=0.82 min, [M+1]⁺=566.16.

Example 38

-   a) A solution of 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (3.0 g, 12.7 mmol, Example 27) in DMF (8 ml) is slowly added to a     suspension of NaH (630 mg, 55% in mineral oil, 1.2 mmol) in DMF (5     ml). The resulting slurry is cooled with an ice-bath before     methyliodide (0.87 ml, 14.0 mmol) is added. The mixture is stirred     at rt for 4 h, diluted with EA and washed with water. The aq. phase     is extracted two more times with EA, the combined organic phase is     dried over Na₂SO₄ and evaporated. The remaining oil crystallises     upon addition of methanol. The crystals are collected, washed with     methanol and dried to give     1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (2.94 g)     as off-white crystals. LC-MS¹: t_(R)=0.71 min, [M+1]⁺=251.06. -   b) 1-Methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (1.03     g, 4.1 mmol) is treated with triethylamine (2.9 ml, 20.5 mmol),     (3,5-dimethoxy-phenoxy)-acetic (1.13 g, 5.33 mmol), and     bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.1 g, 8.2 mmol) as     described in Example 1to furnish     (±)-(1S*,9bS*)-1-benzyloxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (780 mg) as a pale beige powder. ¹H-NMR (300 MHz, CDCl₃): 2.56 (s,     3H), 3.68 (s, 6H), 3.81 (d, J=13.5, 1H), 4.43 (d, J=13.5, 1H), 5.78     (s, 1H), 5.98–6.03 (m, 2H), 6.08–6.12 (m, 1H), 7.22–7.36 (m, 6H),     7.42–7.56 (m, 2H), 7.66–7.71 (m, 1H). LC-MS¹: t_(R)=0.97 min,     [M+1]⁺=445.10. -   c) A solution of     (±)-(1S*,9bS*)-1-benzyloxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4dione     (780 mg, 1.75 mmol) in dioxane (12 ml) and 6 N aq. HCl (8 ml) is     stirred at 70° C. for 2.5 h. The organic solvent is removed under     reduced pressure and the remaining solution is neutralised with aq.     NaOH. The precipitate that forms is collected, and the filtrate is     evaporated. Both, the precipitate and the filtrate are purified by     HPL-chromatography on Rp-C₁₈ silica gel to furnish     (±)-(S*)-(3,5-dimethoxy-phenoxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid (55 mg) as a pale beige solid. LC-MS¹: t_(R)=0.83 min,     [M+1]⁺=463.09.

Example 39

-   a) 7-Chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one is     prepared starting from 2-amino-5-chlorobenzophenone and bromo-acetyl     bromide in analogy to procedures given by M. G. Bock, R. M.     DiPardo, B. E. Evans, K. E. Rittle, D. F. Veber, R. M.     Freidinger, J. Hirshfield, J. P. Springer, J. Org. Chem., 52,     (1987), 3232–3239. LC-MS²: t_(R)=3.96 min, [M+1]⁺=271.00. -   b) 7-Chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (10 g,     36.9 mmol), dissolved in dry DMF (20 ml), is added to a suspension     of NaH (60% in mineral oil) (1.77 g, 44.3 mmol) in dry DMF (60 ml)     at 0° C. The mixture is stirred for 45 min at rt, then cooled to     0° C. and iodomethane (2.53 ml, 40.6 mmol), dissolved in dry DMF (10     ml), is added. The mixture is stirred at rt for 2 h. The suspension     is added to water and extracted three times with EA. The organic     phase is dried over MgSO₄ and evaporated. The crude product is     purified by column chromatography (silicagel, heptane:EA from 4:1 to     2:1) to give of     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (7.1 g) as a light brown solid. LC-MS¹: t_(R)=0.92 min,     [M+1]⁺=284.98. -   c) The [2+2]-cycloaddition is carried out with benzyloxy-acetic acid     as described in Example 18. This furnishes     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     as a pale beige solid. ¹H-NMR (300 MHz, CDCl₃): 2.47 (s, 3H), 3.66     (d, J=13.6, 1H), 4.31 (d, J =13.6, 1 H), 4.39 (s, 2H), 5.11 (s, 1H),     6.91–7.40 (m, 13 H). LC-MS²: t_(R)=1.14 min, [M+1]⁺=432.99. -   d)     (±)-(1S*,9bS*)-1-Benzyloxy-8-chloro-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is subjected to hydrogenolysis as described in Example 18 under 6     atm of H₂ at rt for 6 h. This gives a 5:4 mixture of     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-heptene-2,4-dione     and     (±)-(1S*,9bS*)-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     which is not separated. LC-MS²: t_(R)=0.88 min, [M+1]⁺=342.91;     LC-MS² (dechlorinated product): t_(R)=0.81 min, [M+1]⁺=309.00. -   e) The introduction of the 4,6-dimethoxypyrimidine moiety to the     mixture of     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-heptene-2,4-dione     and     (±)-(1S*,9bS*)-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is performed as described in Example 18. The two products,     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     and     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione,     are separated by column chromatography on silica gel eluting with     heptane: EA 2:1. LC-MS²: t_(R)=1.12 min, [M+1]⁺=481.00; LC-MS²     (dechlorinated product): t_(R)=1.04 min, [M+1]⁺=447.04. -   f)     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is treated with LiOH.H₂O as described in Example 18 to give     (±)-(S*)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid as a white solid. LC-MS²: t_(R)=0.63 min, [M+1]⁺=465.04.

Example 40

-   a) 5-Phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (15.0 g, 63.5     mmol, Example 27) is added in portions to a suspension of NaH (3.05     g, 55% in mineral oil, 76.2 mmol) in DMF (150 ml). The mixture is     diluted with DMF (70 ml). 3,5-Dimethoxybenzylbromide (16.14 g, 69.8     mmol) is added and the mixture is stirred at rt for 16 h. The dark     yellow solution is diluted with EA, washed with water. The aq. phase     is extracted once more with EA, the combined organic phase is dried     over Na₂SO₄ and evaporated. The residue is suspended in diethyl     ether, filtered off, washed with additional diethyl ether and dried     to yield     1-(3,5-dimethoxy-benzyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (14.97 g) as a pale yellow solid. LC-MS²: t_(R)=0.94 min,     [M+1]⁺=387.13. -   b) The [2+2]-cycloaddition is carried out with     1-(3,5-dimethoxy-benzyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (2.45 g, 6.34 mmol) as described in Example 18. Crystallisation of     the product from EA/ethanol gives     (±)-(1S*,9bS*)-1-benzyloxy-5-(3,5-dimethoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (2.0 g) as a pale beige crystals. LC-MS²: t_(R)=1.20 min,     [M+1]⁺=535.07. -   c) In analogy to Example 18, hydrogenolysis of     (±)-(1S*,9bS*)-1-benzyloxy-5-(3,5-dimethoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (2.0 g, 3.7 mmol) at 50° C. under 7 atm H₂ for 20 h furnishes     (±)-(1S*,9bS*)-5-(3,5-dimethoxy-benzyl)-1-hydroxy-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]-cyclobuta[c]cycloheptene-2,4-dione     (1.85 g) as a colourless foam. LC-MS²: t_(R)=0.97 min,     [M+1]⁺=445.05. -   d) The introduction of the 4,6-dimethoxypyrimidine moiety to     (±)-(1S*,     9bS*)-5-(3,5-dimethoxy-benzyl)-1-hydroxy-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]-cyclobuta[c]cycloheptene-2,4-dione     (500 mg, 1.13 mmol) is carried out as described in Example 18. This     gives (±)-(1S*,     9bS*)-5-(3,5-dimethoxy-benzyl)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (357 mg) as a colourless foam. LC-MS²: t_(R)=1.17 min,     [M+1]⁺=583.08. -   e)     (±)-(1S*,9bS*)-5-(3,5-dimethoxy-benzyl)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     (28 mg, 0.048 mmol) is treated with LiOH.H₂O as described in Example     18 to furnish     (±)-(S*)-[(5S*)-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid (14 mg) as a white solid. LC-MS²: t_(R)=0.98 min,     [M+1]⁺=601.12.

Example 41

-   a) 5-Phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (12.0 g, 50.8     mmol, Example 27) is reacted with α-bromo-phenyl-acetic acid methyl     ester (8.77 ml, 55.9 mmol) as described in Example 40 to give     (±)-(2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-phenyl-acetic     acid methyl ester (12.21 g) as a pale pink powder. LC-MS²:     t_(R)=0.98 min, [M+1]⁺=385.11. -   b) The [2+2]-cycloaddition is carried out as described in Example 27     with     (±)-(2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-phenyl-acetic     acid methyl ester (12.20 g, 31.7 mmol) and benzyloxyacetyl chloride     (6.4 ml, 41.3 mmol). This furnishes     (±)-(R/S)-((1S*,9bS*)-1-benzyloxy-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-5-yl)-phenyl-acetic     acid methyl ester (16.73 g) as a pale pink powder. No attempt is     made to separate the diastereoisomers. LC-MS²: t_(R)=1.19 min,     [M+1]⁺=533.21. -   c) Hydrogenolysis of     (±)-(R/S)-((1S*,9bS*)-1-benzyloxy-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[alcyclobuta[c]cyclohepten-5-yl)-phenyl-acetic     acid methyl ester (16.73 mmol, 31.4 mmol) is carried out as     described in Example 27 to give     (±)-(R/S)-((1S*,9bS*)-2,4-dioxo-1-hydroxy-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-5-yl)-phenyl-acetic     acid methyl ester (9.39 g) as a colourless foam. LC-MS²: t_(R)=0.94     min, [M+1]⁺=443.14. -   d) Introduction of the 4,6-dimethoxypyrimidine (Example 8) is     carried out as described in Example 27. This gives     (±)-(R/S)-((1S*,9bS*)[1-(4,6-dimethoxy-pyrimidin-2-yloxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-5-yl]-phenyl-acetic     acid methyl ester as a white powder. LC-MS²: t_(R)=1.04 min,     [M+1]⁺=581.15. -   e) In analogy to Example 27, treatment of     (±)-(R/S)-((1S*,9bS*)[1-(4,6-dimethoxy-pyrimidin-2-yloxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-5-yl]-phenyl-acetic     acid methyl ester (1.5 g, 2.6 mmol) with LiOH.H₂O (271 mg, 6.5 mmol)     at rt for 16 h and at 55° C. for 2 h gives, after HPLC purification,     (±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-[(5S*)-1-((R/S)-methoxycarbonyl-phenyl-methyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid (365 mg) as a white powder. LC-MS²: t_(R)=0.93 min,     [M+1]⁺=599.19.

Example 42

(±)-(R/S)-{(5S*)-5-[(S*)-carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-phenyl-acetic acid (420 mg white powder) is isolated as the second product in step e) of Example 41. LC-MS²: t_(R)=0.83 min, [M+1]⁺=585.17.

Example 43

(±)-(2R/S)-2-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-propionic acid is prepared starting from 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (Example 27) and (±)ethyl 2-bromopropionate in analogy to Example 41. LC-MS²: t_(R)=0.86 min, [M+1]⁺=523.14.

Example 44

-   a) 5-Phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (3.0 g, 12.7     mmol, Example 27) is reacted with acetic acid 2-bromo-ethyl ester     (2.33 g, 14.0 mmol) as described in Example 40 to give acetic acid     2-(2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-ethyl     ester (4.0 g) as a pale yellow oil. LC-MS²: t_(R)=0.81 min,     [M+1]⁺=323.09. -   b)     (±)-(S*)-(4,6-Dimethoxy-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid is prepared starting from acetic acid     2-(2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-ethyl     ester following the procedures given in Example 27. LC-MS²:     t_(R)=0.81 min, [M+1]⁺=495.17.

Example 45

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid methyl ester is prepared starting from 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (Example 27) and 4-bromomethyl-benzoic acid methyl ester following the procedures given in Example 41. LC-MS²: t_(R)=0.92 min, [M+1]⁺=599.22.

Example 46

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid is isolated as a second product in the last step of the preparation of Example 45. LC-MS²: t_(R)=0.81 min, [M+1]⁺=585.19.

Example 47

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-butyric acid is prepared starting from 5-phenyl-1,3dihydro-benzo[e][1,4]diazepin-2-one (Example 27) and 4-bromo-butyric acid ethyl ester following the procedures given in Example 41. LC-MS²: t_(R)=0.73 min, [M+1]⁺=537.17.

Example 48

-   a) (±)-(1S*,     9bS*)-1-Hydroxy-5-(4-methoxy-benzyl)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (2.0 g, 4.8 mmol, Example 26) is reacted with     2-methanesulfonyl-4,6-dimethoxy-pyrimidin (1.26 g, 5.8 mmol,     Example 8) as described in Example 25 to furnish (±)-(1S*,     9bS*)1-(4,6-dimethoxy-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-2-one     (2.49 g) as a white powder. LC-MS¹: t_(R)=1.18 min, [M+1]⁺=553.10. -   b) A solution of a ammonium cerium(IV)nitrate (7.41 g, 13.5 mmol) in     water (25 ml) is added at 0° C. to a suspension of (±)-(1S*,     9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-2-one     (2.49 g, 4.5 mmol) in acetonitrile (60 ml). The mixture is stirred     at rt for 4 h, diluted with water and extracted three times with     DCM. The organic phase is washed twice with water, three times with     brine, dried over MgSO₄ and evaporated. The remaining residue is     suspended in diethyl ether, collected, washed with additional     diethyl ether and dried to give (±)-(1S*,     9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one     (1.45 g) as a white powder. LC-MS¹: t_(R)=0.98 min, [M+1]⁺=433.03. -   c) A mixture of (±)-(1S*,     9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]-cyclohepten-2-one     (216 mg, 0.5 mmol), K₂CO₃ (208 mg, 1.5 mmol) and     2,4,6-trifluorobenzyl bromide (169 mg, 0.75 mmol) is stirred at     60° C. for 18 h. Further 2,4,6-trifluoroenzyl bromide (50 mg) and     K₂CO₃ (50 mg) is added and stirring is continued at 50° C. for 18 h.     The mixture is diluted with water, extracted twice with EA. The     organic phase is washed with brine, dried over MgSO₄ and evaporated.     The crude product is purified by chromatography on prep. tlc plates     with EA:heptane 7:3 to furnish (±)-(1S*,     9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-5-(2,4,6-trifluoro-benzyl)-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]-cyclohepten-2-one     (268 mg) as an almost colourless foam. LC-MS¹: t_(R)=1.18 min,     [M+1]⁺=577.05. -   d) (±)-(1S*,     9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-5-(2,4,6-trifluoro-benzyl)-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]-cyclohepten-2-one     (260 mg, 0.45 mmol) is treated with LiOH.H₂O (2 ml of 2N aq.     solution) as described in Example 25 to give     (±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-[(5S*)-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid (150 mg) as a colourless foam. LC-MS¹: t_(R)=1.08 min,     [M+1]⁺=595.06.

Example 49

(±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid is prepared in analogy to Example 39. LC-MS¹: t_(R)=0.82 min, [M+1]⁺=433.05.

Example 50

-   a) To a suspension of NaH (60% in mineral oil) (230 mg, 5.75 mmol)     in dry DMF (15 ml) 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (1.0 g, 4.23 mmol, Example 38) is added in two portions. The mixture     is diluted with dry DMF (40 ml) and ethyl bromoacetate (932 mg, 6.09     mmol) is added. The mixture becomes clear again upon stirring at     room temperature for 1 h and is diluted with EA. The organic phase     is washed with water, the aqueous phase is extracted with EA. The     combined organic phase is washed three more times with water, dried     over MgSO₄ and evaporated. The resulting oil is treated several     times with hexane which is decanted. The remaining orange oil is     dried under vacuum to give     (2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-acetic acid     ethyl ester (1.2 g) as a yellow foam/gum. LC-MS²: t_(R)=4.09 min     [M+1]⁺=323.20. -   b) To a solution of     (2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-acetic acid     ethyl ester (1.2 g, 3.72 mmol) in dry DCM (20 ml) is added     benzyloxy-acetic acid (928 mg, 5.58 mmol, Example 18) followed by     triethylamine (2.59 ml, 18.6 mmol). The solution is cooled with an     ice-bath and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.90 g,     7.46 mmol) is added in two portions. The mixture is stirred at 0° C.     and is allowed to slowly come to rt. Stirring is continued for 16 h     before the mixture is diluted with DCM and washed with sat. aq.     NaHCO₃. The aqueous phase is extracted twice with DCM. The combined     organic phase is dried over MgSO₄ and evaporated. The crude product     is purified by column chromatography (silica gel, heptane:EA 1:1) to     give (±)-((1S*,     9bS*)-1-benzyloxy-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5′-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl)-acetic     acid ethyl ester (1.56 g) as an almost colourless foam. LC-MS²:     t_(R)=5.04 min, [M+1]⁺=471.29. -   c) To a suspension of 10% Pd on charcoal (250 mg) in ethanol (5 ml)     a solution of (±)-((1S*,     9bS*)-1-benzyloxy-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5′-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl)-acetic     acid ethyl ester (1.55 g, 3.29 mmol) in ethanol (15 ml) and THF     (5 ml) is added and the resulting reaction mixture is stirred at rt     for 1 h under 2 atm of H₂. Then acetic acid (0.5 ml, 8.74 mmol) is     added and stirring is continued at 40° C. for 16 h under 7 atm of     H₂. Further 10% Pd on charcoal (200 mg), suspended in ethanol (3     ml), is added and stirring is continued for another 5 h at 40° C.     under 7 atm of H₂. The catalyst is filtered off through celite and     the colourless filtrate is evaporated to give (±)-((1S*,     9bS*)-1-hydroxy-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-5-yl)-acetic     acid ethyl ester (1.25 g) as a colourless foam. LC-MS²: t_(R)=3.86     min, [M+1]⁺=381.29, [M−1]⁻=379.09. -   d) To a suspension of NaH (60% in mineral oil) (60 mg, 1.5 mmol) in     dry THF (6 ml) and dry DMF (2 ml) (±)-((1S*,     9bS*)-hydroxy-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl)-acetic     acid ethyl ester (400 mg, 1.05 mmol) is added. The mixture is     stirred at rt for 10 min before     2-methanesulfonyl-4,6-dimethyl-pyrimidine (Example 7b) (255 mg, 1.37     mmol) is added. Stirring is continued for 6 h. Further NaH (30 mg,     750 μmol) and 2-methanesulfonyl-4,6-dimethyl-pyrimidine (100 mg, 537     μmol) is added. After 2 h at rt the reaction mixture is diluted with     EA, washed with sat. aq. NaHCO₃, followed twice by water. The     organic phase is evaporated and dried before it is dissolved again     in dry THF (6 ml) and dry DMF (2 ml). NaH (50 mg, 1.25 mmol)     followed by 2-methanesulfonyl-4,6-dimethyl-pyrimidine (180 mg, 967     μmol) is added and the resulting mixture is stirred at rt for 45 min     The reaction mixture is extracted again as described above. The     organic phase is evaporated. The resulting oil is purified by column     chromatography (silica gel, heptane:EA 1:1) to give (±)-[(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-yl]-acetic     acid ethyl ester (483 mg) as a colourless foam. LC-MS²: t_(R)=4.74     min, [M+1]⁺=487.14, [M−1]⁻=484.90. -   e) A solution of (±)-(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-yl]-acetic     acid ethyl ester (250 mg, 514 μmol) in THF (8 ml), methanol (6 ml)     and 2 N aq. lithium hydroxyde (4 ml) is stirred at 65° C. for 2 h.     The organic solvents are evaporated and the remaining solution is     acidified by adding of 10% aq. acetic acid (8 ml), diluted with     water (10 ml) and washed three times with DCM. The aqueous phase is     partially evaporated and the crude product is purified by     preparative HPLC to give     (±)-(S*)-((5S*)-1-Carboxymethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetoc     acid (58 mg) as a white lyophilisate. LC-MS²: t_(R)=3.40 min,     [M+1]⁺=477.39, [M−1]⁻=475.08.

Example 51

(±)-(S*)-[(5S*)-1-(3,5-Dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 40. LC-MS¹: t_(R)=0.88 min, [M+1]⁺=569.22.

Example 52

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-((R/S)-methoxycarbonyl-phenyl-methyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Example 41. LC-MS¹: t_(R)=0.88 min, [M+1]⁺=567.19.

Example 53

(±)-(S*)-[(5S*)-1-((R/S)-Carboxy-phenyl-methyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 42. LC-MS¹: t_(R)=0.79 min, [M+1]⁺=553.17.

Example 54

(±)-(2R/S)-2-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-propionic acid ethyl ester is prepared in analogy to Example 43. LC-MS¹: t_(R)=0.84 min, [M+1]⁺=519.28.

Example 55

(±)-(R/S)-2-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-propionic acid is prepared in analogy to Example 43. LC-MS¹: t_(R)=0.73 min, [M+1]⁺=491.24.

Example 56

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Example 44. LC-MS¹: t_(R)=0.77 min, [M+1]⁺=462.16.

Example 57

-   a) (±)-[(1S*,     9bS*)-1-(4,6-Dimethyl-pyrimidin-2-yloxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl]-acetonitrile     is prepared in analogy to Example 40 starting from     5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (Example 27) and     chloroacetonitrile. LC-MS¹: t_(R)=0.96 min, [M+1]⁺=440.14. -   b) A mixture of (±)-[(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-hepten-5-yl]-acetonitrile     (150 mg, 0.34 mmol), NaN₃ (23 mg, 0.36 mmol) and NH₄Cl (20 mg, 0.38     mmol) in DMF (4 ml) is stirred at 60° C. for 1 h. Additional NaN₃     (23 mg) and NH₄Cl (20 mg) is added and stirring is conitued for     17 h. Once more, NaN₃ (23 mg) and NH₄Cl (20 mg) is added and the     mixture is stirred at 60° C. for additional 8 h before it is diluted     with 1 N aq. HCl and extracted three times with EA. The organic     phase is dried over MgSO₄ and evaprorated to give (±)-(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-5-(1H-tetrazol-5-ylmethyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (160 mg) as a white solid. LC-MS¹: t_(R)=0.88 min, [M+1]⁺=483.17. -   c) (±)-(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-5-(1H-tetrazol-5-ylmethyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (160 mg) is treated with LiOH.H₂O (2 ml of a 2 N aq. solution) as     described in Example 27 to give     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(1H-tetrazol-5-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid (96 mg) as a white powder. LC-MS¹: t_(R)=0.79 min,     [M+1]⁺=501.19.

Example 58

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid methyl ester is prepared in analogy to Example 45. LC-MS¹: t_(R)=0.87 min, [M+1]⁺=567.20.

Example 59

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid is prepared in analogy to Example 46. LC-MS¹: t_(R)=0.77 min, [M+1]⁺=553.18.

Example 60

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-butyric acid is prepared in analogy to Example 47. LC-MS¹: t_(R)=0.70 min, [M+1]⁺=505.17.

Example 61

(±)-(1S*, 9bS*)-1-(4,6-dimethylpyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one (200 mg, 0.38 mmol, prepared in analogy to Example 48) is treated with LiOH.H₂O (1.5 ml of a 2 N aq. solution) as described in Example 25 to furnish (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid (223 mg) as a white solid. LC-MS²: t_(R)=4.32 min, [M+1]⁺=539.47, [M−1]⁻=536.85.

Examples 62 to 116

Examples 62 to 116 are prepared starting from (±)-(1S*, 9bS*)-1-(4,6-dimethylpyrimidin-2-yloxy)-9b-phenyl-3,4,5,9b-tetrahydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-2-one and the appropriate alkylating agent in analogy to the procedures given in Exampe 48.

Ex- am- t_(R) (LC-MS¹) ple R [min] [M + 1]⁺ 62

0.85 577.07 63

0.81 473.13 64

0.92 543.08 65

1.13 645.05 66

0.63 532.12 67

1.01 585.12 68

0.92 576.13 69

0.63 490.13 70

0.93 565.16 71

0.87 542.98 72

0.82 543.05 73

0.84 577.06 74

0.85 593.09 75

0.86 593.07 76

0.84 577.04 77

0.77 527.10 78

0.78 523.11 79

0.78 566.03 80

0.67 514.07 81

0.62 560.09 82

0.84 503.10 83

0.87 593.08 84

0.75 663.08 85

0.74 562.12 86

0.84 586.98 87

0.80 553.11 88

0.77 527.08 89

0.76 545.04 90

0.81 537.11 91

0.77 527.08 92

0.83 587.00 93

0.62 521.08 94

0.79 523.08 95

0.81 523.09 96

0.81 523.06 97

0.89 529.12 98

0.84 515.08 99

0.80 545.03 100

0.80 545.04 101

0.85 537.16 102

0.80 545.09 103

0.80 545.06 104

0.78 544.99 105

0.82 598.99 106

0.77 563.03 107

0.78 563.06 108

0.76 509.04 109

1.04 541.07 110

0.59 476.07 111

1.15 551.12 112

1.05 563.07 113

1.23 565.15 114

1.11 604.99 115

1.06 577.03 116

1.16 577.03

Example 117

-   a) 2-Phenylamino-benzophenone acid is prepared from 2-amino     benzophenone according to a procedure described in the literature     (J. C. Antilla, S. L. Buchwald, Org. Lett. 2 (2001), 2077–2079).     ¹H-NMR(300 MHz, CDCl₃): 6.69 (dt, J_(t)=7.0, J_(d)=1.2, 1H), 7.10     (t, J=7.6, 1H), 7.2–7.4 (m, 5H), 7.4–7.6 (m, 5H), 7.69 (d, J=7.0,     2H). LC-MS²: t_(R)=6.13 min, [M+1]⁺=274. -   b) To a cooled (0° C.) solution of 2-phenylamino-benzophenone (2.73     g, 10 mmol) in DCM (24 ml), are added water (5 ml) followed by     bromoacetyl bromide (2.0 ml, 23 mmol). Stirring is continued at rt     for 15 hrs. The layers are partitioned and the organic phase washed     with brine, dried over MgSO₄ and the solvent removed in vacuo to     yield N-(2-benzoyl-phenyl)-2-bromo-N-phenyl-acetamide (3.84 g),     which is not further purified. LC-MS²: t_(R)=5.27 min, [M+1]⁺=394. -   c) N-(2-Benzoyl-phenyl)-2-bromo-N-phenyl-acetamide (0.27 g, 0.68     mmol) is dissolved in ammonia saturated methanol (7N) and heated to     45° C. for 15 h. The solvent is removed in vacuo, the crude product     dissolved in DCM, washed with water, brine, dried over MgSO₄ and the     solvent removed in vacuo. The crude product is purified over column     chromatography on silica (10% EtOAc in Heptane) to afford     1,5-diphenyl-1,3-dihydro-benzo[b]azepin-2-one (0.1 g). ¹H-NMR(300     MHz, CDCl₃): 4.01 (d, J=9.9, 1H), 4.94 (d, J=9.9, 1H), 6.96 (d,     J=8.8, 1H), 7.2–7.5 (m, 11H), 7.7 (m, 2H). LC-MS²: t_(R)=4.57 min,     [M+1]⁺=313. -   d) Triethylamine (0.225 ml, 1.60 mmol) is added dropwise to a cooled     (0° C.) solution of 1,5-diphenyl-1,3-dihydro-benzo[b]azepin-2-one     (0.1 g, 0.320 mmol) and benzyloxy acetyl chloride (0.066 ml, 0.416     mmol) in DCM (3 ml). The ice bath is allowed to warm to rt over     15 h. The reaction mixture is diluted with EA, extracted with sat.     aq. NaHCO₃, the aq. phase is extracted with EA (2×). The combined     organic phases are washed with brine, dried over MgSO₄ and the     solvent removed in vacuo to give (±)-(1S*,     9bS*)-1-benzyloxy-5,9b-diphenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.13 g) as a light yellow foam. ¹H-NMR(300 MHz, CDCl₃): 4.03 (d,     J=12.8, 1H), 4.12 (s, 1H), 4.50 (d, J=11.1, 1H), 4.58–4.66 (m, 2H),     5.4 (s, 1H), 6.85 (m, 1H), 6.88 (dd, J=1.6, 7.3, 1H), 7.0–7.2 (m,     5H), 7.2–7.5 (m, 8H). LC-MS²: t_(R)=5.3 min, [M+1]⁺=461. -   e) To Pd/C (0.03 g, 10%) are added (±)-(1S*,     9bS*)-1-benzyloxy-5,9b-diphenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.13 g, 0.283 mmol), THF (0.8 ml), ethanol (2 ml) and acetic acid     (0.03 ml). The reaction mixture is stirred at 50° C. under 7 atm H₂     for 20 h. The Pd-catalyst is filtered and the solvent removed in     vacuo to afford (±)-(1S*,     9bS*)-1-hydroxy-5,9b-diphenyl-5,9b-dihydro-1H-2a,5-diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.07 g) as a white powder, which is used without further     purification. LC-MS²: t_(R)=4.04 min, [M+1]⁺=371. -   f) K₂CO₃ (4.89 g, 35.4 mmol) is added to a solution of (±)-(1S*,     9bS*)-1-hydroxy-5,9b-diphenyl-5,9b-dihydro-1H-2a,5-diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.07 g, 0.189 mmol) and 2-methanesulfonyl-4,6-dimethy-pyrimidine     (0.042 g, 0.226 mmol, Example 19) in DMF (2 ml). The resulting     suspension is heated to 50° C. over 48 h, diluted with DCM, washed     with water (2×), brine (2×), dried over MgSO₄ and the solvent     removed in vacuo. The crude product is suspended in EA to yield     (±)-(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5,9b-diphenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.05 g) as a white powder. LC-MS²: t_(R)=4.90 min, [M+1]⁺=477. -   g) LiOH.H₂O (0.067 ml of a 2N aq. solution) is added to a solution     of (±)-(1S*,     9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5,9b-diphenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.05 g, 0.105 mmol) in THF (0.55 ml) and methanol (0.2 ml). The     mixture is stirred at rt for 15 h, the pH is adjusted to pH=5 with 1     N HCl and the solvents removed in vacuo. The crude product is     purified by prep. tlc on silica (5% MeOH in CH₂Cl₂) to afford     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-1,5-diphenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid (0.024 g) as a pale yellow powder. ¹H-NMR(300 MHz, CDCl₃): 2.23     (s, 6H), 3.4–3.8 (m, 2H), 6.4–6.6 (m, 3H), 6.89 (s, 1H), 7.0–75 (m,     12H). LC-MS²: t_(R)=4.97 min, [M+1]⁺=495.

Example 118

-   (±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic     acid methyl ester is prepared in analogy to Examples 29 and 45.     LC-MS¹: t_(R)=0.96 min, [M+1]⁺=595.25.

Example 119

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid is prepared in analogy to Examples 29 and 46. LC-MS¹: t_(R)=0.84 min, [M+1]⁺=581.22.

Example 120

(±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-butyric acid is prepared in analogy to Examples 29 and 47. LC-MS¹: t_(R)=0.76 min, [M+1]⁺=533.21.

Example 121

(±)-(S*)-(4,6-Diethyl-pyrimidin-2-yloxy)-[(5S*)-1-((R/S)-methoxycarbonyl-phenyl-methyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared as a racemic mixture of diastereoisomers in analogy to Examples 29 and 41. LC-MS¹: t_(R)=0.96 min, [M+1]⁺=595.26.

Example 122

(±)-(2R/S)-2-{(5S*)-5-[(S*)-Carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-propionic acid ethyl ester is prepared as a racemic mixture of diastereoisomers in analogy to Examples 29 and 43. LC-MS¹: t_(R)=0.92 min, [M+1]⁺=547.19.

Example 123

(±)-(2R/S)-2-{(5S*)-5-[(S*)-Carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-propionic acid is prepared as a racemic mixture of diastereoisomers in analogy to Examples 29 and 43. LC-MS¹: t_(R)=0.79 min, [M+1]⁺=519.15.

Example 124

(±)-(S*)-(4,6-Diethyl-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Examples 29 and 44. LC-MS¹: t_(R)=0.74 min, [M+1]⁺=491.16.

Example 125

(±)-(S*)-(4,6-Diethyl-pyrimidin-2-yloxy)-[(5S*)-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Examples 29 and 40. LC-MS¹: t_(R)=1.02 min, [M+1]⁺=597.27.

Example 126

(±)-(S*)-(4,6-Diethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Examples 29 and 48. LC-MS²: t_(R)=5.02 min, [M+1]⁺=591.39, [M−1]⁻=589.29.

Example 127

Pd/C (100 mg, 10% Pd) is added to a solution of (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid (100 mg, 0.231 mmol, Example 49) in water (8 ml), methanol (8 ml) and aq. formaldehyde solution (0.2 ml, 36%). The mixture is stirred at rt under 3 atm H₂ for 18 h before the catalyst is filtered off. The organic solvent of the filtrate is evaporated and the remaining aq. phase is extracted three times with DCM. The organic phase is evaporated and the product is purified by chromatography on prep. tlc-plattes with DCM:methanol 9:1 to give (±)-(S*)-((5S*)-1,4-dimethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (57 mg) as a white powder. LC-MS²: t_(R)=3.40 min, [M+1]⁺=447.10, [M−1]⁻=445.14.

Example 128

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-4-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared starting from (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid (Example 61) in analogy to Example 127. LC-MS¹: t_(R)=0.95 min, [M+1]⁺=553.16.

Example 129

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-4-methyl-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared starting from (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid (Example 107) in analogy to Example 127. LC-MS¹: t_(R)=1.06 min, [M+1]⁺=577.00.

Example 130

(±)-(S*)-((5S*)-4-ethyl-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared starting from (±)-(S*)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (Example 49) and acetaldehyde in analogy to Example 127. LC-MS¹: t_(R)=0.75 min, [M+1]⁺=461.16.

Example 131

Sodium methylate (10.14 g, 186 mmol) is added at 0° C. to a solution of (±)-(1S*, 9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (5.0 g, 12 mmol, Example 49) in methanol (250 ml). The solution is stirred at rt for 3 h, poured into a solution of citric acid (12.6 g, mono hydrate) in water (600 ml) and extracted three times with EA. The organic phase is washed with brine, dried over MgSO₄ and evaporated to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid methyl ester (5.04 g) as a white foam. LC-MS¹: t_(R)=0.94 min, [M+1]⁺=447.07.

Example 132

(±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid ethyl ester is prepared in analogy to Example 131. LC-MS¹: t_(R)=0.89 min, [M+1]⁺=461.13.

Example 133

(±)-(S*)-[(5S*)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid methyl ester is prepared starting from (±)-(1S*,9bS*)-5-(3,5-bis-trifluoromethyl-benzyl)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 65) in analogy to Example 131. LC-MS¹: t_(R)=1.24 min, [M+1]⁺=659.02.

Example 134

(±)-(S*)-[(5S*)-1-(2,6-Difluoro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid methyl ester is prepared starting from (±)-(1S*,9bS*)-5-(2,6-difluoro-benzyl)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 89) in analogy to Example 131. LC-MS¹: t_(R)=1.13 min, [M+1]⁺=559.06.

Example 135

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-((5S*)-2-oxo-1-phenethyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid methyl ester is prepared starting from (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-phenethyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 78) in analogy to Example 131. LC-MS¹: t_(R)=1.14 min, [M+1]⁺=537.07.

Example 136

-   a)     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid methyl ester (447 mg, 1 mmol, Example 131) is added to a     mixture of acetic anhydride (1.9 ml) and formic acid (0.76 ml) at     5° C. The mixture is stirred at rt for 1 h before it is poured into     cold sat. aq. NaHCO₃. The aq. phase is extracted three times with     EA. The organic phase is washed with brine, dried over MgSO₄ and     evaporated. The crude product is purified by chromatography on prep.     tlc plates with DCM:methanol 9:1 to furnish     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-4-formyl-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid methyl ester (210 mg) as a colourless foam. LC-MS¹: t_(R)=0.97     min, [M+1]⁺=475.06. -   b) A solution of     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-4-formyl-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid methyl ester (200 mg, 0.42 mmol) in THF (6 ml), methanol (3     ml), and 2 N aq. LiOH (1 ml) is stirred at rt for 1 h. The solution     is poured into 10% aq. citric acid, extracted three times with EA.     The organic phase is washed with brine, dried over MgSO₄, evaporated     and dried under HV to yield     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-4-formyl-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid (220 mg) as a colourless foam. LC-MS¹: t_(R)=0.89 min,     [M+1]⁺=461.04.

Example 137

-   a)     (±)-(1S*,9bS*)-8-Chloro-5-methyl-1-phenoxy-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and phenoxy-acetic acid in analogy to Example 18.     LC-MS²: t_(R)=5.05 min, [M+1]⁺=419.16, [M−1]⁻=417.08. -   b)     (±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-phenoxy-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-5-methyl-1-phenoxy-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 38. LC-MS²: t_(R)=4.41 min, [M+1]⁺=437.21,     [M−1]⁻=435.19.

Example 138

-   a) (4-Methoxy-phenoxy)-acetic acid ethyl ester is prepared from     4-methoxy-phenol and bromo-acetic acid ethyl ester in analogy to     Example 1. LC-MS²: t_(R)=4.18 min, [M+1]⁺=211.06. -   b) (4-Methoxy-phenoxy)-acetic acid is obtained from     (4methoxy-phenoxy)-acetic acid ethyl ester in analogy to Example 1.     LC-MS²: t_(R)=3.09 min, [M−1]⁻=181.04. -   c)     (±)-(1S*,9bS*)-8-Chloro-1-(4-methoxy-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and (4-methoxy-phenoxy)-acetic acid according to     Example 18. LC-MS¹: t_(R)=1.01 min, [M+1]⁺=449.08. -   d)     (±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl)-(4-methoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-1-(4-methoxy-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=0.89 min, [M+1]⁺=467.09.

Example 139

-   a) (4-Chloro-phenoxy)-acetic acid ethyl ester is prepared from     4-chloro-phenol and bromo-acetic acid ethyl ester in analogy to     Example 1. -   b) (4-Chloro-phenoxy)-acetic acid is obtained from     (4-chloro-phenoxy)-acetic acid ethyl ester according to Example 1. -   c)     (±)-(1S*,9bS*)-8-Chloro-1-(4-chloro-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and (4-chloro-phenoxy)-acetic acid according to     Example 18. LC-MS¹: t_(R)=1.19 min, [M+1]⁺=453.01. -   d)     (±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl)-(4-chloro-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-1-(4-chloro-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=1.07 min, [M+1]⁺=471.00.

Example 140

-   a) (4-Bromo-phenoxy)-acetic acid ethyl ester is prepared from     4-bromo-phenol and bromo-acetic acid ethyl ester in analogy to     Example 1. -   b) (4-Bromo-phenoxy)-acetic acid is obtained from     (4-bromo-phenoxy)-acetic acid ethyl ester according to Example 1 b).     LC-MS²: t_(R)=3.78 min, [M−1]⁻=228.91. -   c)     (±)-(1S*,9bS*)-1-(4-Bromo-phenoxy)-8-chloro-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and (4-bromo-phenoxy)-acetic acid according to     Example 18. LC-MS¹: t_(R)=1.10 min, [M+1]⁺=498.93. -   d)     (±)-(S*)-(4-Bromo-phenoxy)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid is prepared from     (±)-(1S*,9bS*)-1-(4-bromo-phenoxy)-8-chloro-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=0.97 min, [M+1]⁺=516.89.

Example 141

-   a) p-Tolyloxy-acetic acid ethyl ester is prepared from     4-methyl-phenol and bromo-acetic acid ethyl ester in analogy to     Example 1. -   b) p-Tolyloxy-acetic acid is obtained from p-tolyloxy-acetic acid     ethyl ester according to Example 1. -   c)     (±)-(1S*,9bS*)-8-Chloro-5-methyl-9b-phenyl-1-p-tolyloxy-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and p-tolyloxy-acetic acid according to Example 18.     LC-MS²: t_(R)=5.25 min, [M+1]⁺=433.04. -   d)     (±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl)-p-tolyloxy-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-5-methyl-9b-phenyl-1-p-tolyloxy-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=0.94 min, [M+1]⁺=451.04.

Example 142

-   a) 4-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester is     prepared from 4-hydroxy-benzoic acid methyl ester and bromo-acetic     acid tert-butyl ester in analogy to Example 1.

b) To a solution of 4-tert-butoxycarbonylmethoxy-benzoic acid methyl ester (5 g, 18.8 mmol) in dry DCM (40 ml) is added trifluoro-acetic acid (40 ml) at 0° C. The solution is stirred for 5 h at rt and evaporated in vacuo to give 4-carboxymethoxy-benzoic acid methyl ester 4 g as a white solid. LC-MS²: t_(R)=3.24 min, [M+1]⁺=211.04, [M−1]⁻=208.96.

-   c)     (±)-4-((1S*,9bS*)-8-Chloro-5-methyl-2,4-dioxo-9b-phenyl-1,2,3,4,5,9b-hexahydro-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-1-yloxy)-benzoic     acid methyl ester is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and 4-carboxymethoxy-benzoic acid methyl ester     according to Example 18. LC-MS¹: t_(R)=1.11 min, [M+1]⁺=477.07. -   d)     (±)-4-[(S*)-Carboxy-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-methoxy]-benzoic     acid is prepared from     (±)-(1S*,9bS*)-4-(8-chloro-5-methyl-2,4-dioxo-9b-phenyl-1,2,3,4,5,9b-hexahydro-2a,5-diaza-benzo[a]cyclobuta[c]cyclohepten-1-yloxy)-benzoic     acid methyl ester in analogy to Example 18. LC-MS¹: t_(R)=0.88 min,     [M+1]⁺=481.04.

Example 143

(±)-4-[(S*)-Carboxy-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-methoxy]-benzoic acid methyl ester is isolated as a second product in Example 142. LC-MS¹: t_(R)=0.99 min, [M+1]⁺=495.04.

Example 144

-   a) (3-Methoxy-phenoxy)-acetic acid ethyl ester is prepared from     3-methoxy-phenol and bromo-acetic acid ethyl ester in analogy to     Example 1. -   b) (3-Methoxy-phenoxy)-acetic acid is obtained from     (3-methoxy-phenoxy)-acetic acid ethyl ester according to Example 1. -   c)     (±)-(1S*,9bS*)-8-Chloro-1-(3-methoxy-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and (3-methoxy-phenoxy)-acetic acid according to     Example 18. LC-MS¹: t_(R)=1.12 min, [M+1]⁺=449.03. -   d)     (±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3-methoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-1-(3-methoxy-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=0.77 min, [M+1]⁺=467.05.

Example 145

-   a) 3-Carboxymethoxy-benzoic acid methyl ester is prepared from     3-tert-butoxycarbonylmethoxy-benzoic acid methyl ester as described     in Example 1. LC-MS²: t_(R)=3.29 min, [M−1]⁻=208.97. -   b)     (±)-3-[(S*)-Carboxy-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-methoxy]-benzoic     acid is prepared in analogy to Example 142. LC-MS¹: t_(R)=0.89 min,     [M+1]⁺=481.04.

Example 146

(±)-3-[(S*)-Carboxy-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-methoxy]-benzoic acid methyl ester is prepared in analogy to Example 143. LC-MS¹: t_(R)=1.00 min, [M+1]⁺=495.04.

Example 147

-   a) (3,5-Dichloro-phenoxy)-acetic acid is obtained from     (3,5-dichloro-phenoxy)-acetic acid ethyl ester according to Example     1. -   b)     (±)-(1S*,9bS*)-8-Chloro-1-(3,5-dichloro-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and (3,5-dichloro-phenoxy)-acetic acid according to     Example 18. LC-MS¹: t_(R)=1.28 min, [M+1]⁺=527.86; ¹H-NMR (300 MHz,     CDCl₃): 2.53 (s, 3H), 3.81 (d, J=13.5, 1H), 4.44 (d, J=13.5, 1H),     5.67 (s, 1H), 6.79 (d, J=1.9, 2H), 7.00 (t, J=1.9, 1H), 7.19 (d,     J=8.7, 1H), 7.33 (br, 5H), 7.50 (dd, J=2.4, 8.4, 1H), 7.57 (d,     J=2.3, 1H). -   c) Lithium hydroxyde monohydrate (31 mg, 742 μmol), dissolved in     water (500 μl), is added to a solution of     (±)-(1S*,9bS*)-8-chloro-1-(3,5-dichloro-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     (300 mg, 618 μmol) in THF (2 ml) and methanol (500 μl). The solution     is stirred for 1 h at rt, then diluted with water and the organic     solvents are evaporated in vacuo. The solution is acidified to pH 6     and the mixture lyophilized. The residue is purified by prep. HPLC     to give     (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dichloro-phenoxy)-acetic     acid (78 mg) as a white powder. LC-MS¹: t_(R)=1.13 min,     [M+1]⁺=506.92.

Example 148

-   a) (3,5-Dimethyl-phenoxy)-acetic acid is obtained from     (3,5-dimethyl-phenoxy)-acetic acid ethyl ester in analogy to Example     1. -   b)     (±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethyl-phenoxy)-acetic     acid is prepared in analogy to Example 18. LC-MS¹: t_(R)=0.98 min,     [M+1]⁺=465.07.

Example 149

-   a)     (±)-(1S*,9bS*)-8-Chloro-1-(3,5-dimethoxy-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and from (3,5-dimethoxy-phenoxy)-acetic acid     (Example 1) according to Example 18. LC-MS²: t_(R)=5.04 min,     [M+1]⁺=479.29, [M−1]⁻=477.42. -   b) A solution of     (±)-(1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     (670 mg, 1.39 mmol) in dioxane (8 ml) and 6 M aq. HCl (6 ml) is     heated for 2.5 h at 80° C. After cooling to rt the pH of the     solution is adjusted to 7 and the solvents are evaporated. The     residue is purified by MPLC to give     (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid (42 mg, 85 μmol) as a white solid. LC-MS²: t_(R)=4.51 min,     [M+1]⁺=497.21, [M−1]⁻=495.19.

Example 150

-   a) 7-Chloro-1-ethyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and iodo-ethane according to Example 39. LC-MS¹:     t_(R)=0.88 min, [M+1]⁺=299.09. -   b)     (±)-(1S*,9bS*)-8-Chloro-1-(3,5-dimethoxy-phenoxy)-5-ethyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-ethyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) in analogy to     Example 18. LC-MS¹: t_(R)=1.18 min, [M+1]⁺=493.07. -   c)     (±)-(S*)-((5S*)-7-Chloro-1-ethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-5-ethyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=1.05 min, [M+1]⁺=511.06.

Example 151

-   a)     7-Chloro-5-phenyl-1-propyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and 1-bromo-propane according to Example 39. LC-MS¹:     t_(R)=0.92 min, [M+1]⁺=313.03. -   b)     (±)-(1S*,9bS*)-8-Chloro-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5-propyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-5-phenyl-1-propyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) according to     Example 18. LC-MS¹: t_(R)=1.22 min, [M+1]⁺=507.09. -   c)     (±)-(S*)-((5S*)-7-Chloro-2-oxo-5-phenyl-1-propyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5-propyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=1.10 min, [M+1]⁺=525.07.

Example 152

-   a)     7-Chloro-1-isopropyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and 2-iodo-propane according to Example 39. LC-MS¹:     t_(R)=0.91 min, [M+1]⁺=313.01. -   b)     (±)-(S*)-((5S*)-7-Chloro-1-isopropyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared in analogy to Example 18. LC-MS¹: t_(R)=1.09 min,     [M+1]⁺=525.06.

Example 153

-   a)     (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-acetonitrile     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and chloro-acetonitrile in analogy to Example 39.     LC-MS¹: t_(R)=0.90 min, [M+1]⁺=309.97. -   b)     (±)-(1S*,9bS*)-[8-Chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl]-acetonitrile     is prepared from     (7-chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-acetonitrile     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) in analogy to     Example 18. LC-MS¹: t_(R)=0.99 min, [M+1]⁺=504.03. -   c)     (±)-(S*)-((5S*)-7-Chloro-1-cyanomethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-[8-chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-yl]-acetonitrile     in analogy to Example 18. LC-MS¹: t_(R)=1.08 min, [M+1]⁺=522.02.

Example 154

-   a)     7-Chloro-5-phenyl-1-prop-2-ynyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and 3-bromo-propyne according to Example 39. LC-MS¹:     t_(R)=0.91 min, [M+1]⁺=308.98. -   b)     (±)-(1S*,9bS*)-8-Chloro-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5-prop-2-ynyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-5-phenyl-1-prop-2-ynyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) according to     Example 18. LC-MS¹: t_(R)=1.16 min, [M+1]⁺=503.05. -   c)     (±)-(S*)-((5S*)-7-Chloro-2-oxo-5-phenyl-1-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5-prop-2-ynyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=1.07 min, [M+1]⁺=521.03.

Example 155

-   a)     1-Benzyl-7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and bromomethyl-benzene according to Example 39.     LC-MS¹: t_(R)=0.98 min, [M+1]⁺=361.03. -   b)     (±)-(1S*,9bS*)-5-Benzyl-8-chloro-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     1-benzyl-7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) according to     Example 18. LC-MS¹: t_(R)=1.26 min, [M+1]⁺=555.09. -   c)     (±)-(S*)-((5S*)-1-Benzyl-7-chloro-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-5-benzyl-8-chloro-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=1.17 min, [M+1]⁺=573.08.

Example 156

-   a)     7-Chloro-1-(3,5-dimethoxy-benzyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and 1-bromomethyl-3,5-dimethoxy-benzene according to     Example 39. LC-MS¹: t_(R)=1.12 min, [M+1]⁺=421.03. -   b)     (±)-(1S*,9bS*)-8-Chloro-5-(3,5-dimethoxy-benzyl)-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is prepared from     7-chloro-1-(3,5-dimethoxy-benzyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) according to     Example 18. LC-MS¹: t_(R)=1.24 min, [M+1]⁺=615.05. -   c)     (±)-(S*)-[(5S*)-7-Chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-5-(3,5-dimethoxy-benzyl)-1-(3,5-dimethoxy-phenoxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=1.16 min, [M+1]⁺=633.07.

Example 157

-   a) Acetic acid     2-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-ethyl     ester is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and acetic acid 2-bromo-ethyl ester according to     Example 39. LC-MS¹: t_(R)=0.98 min, [M+1]⁺=356.99; ¹H-NMR (300 MHz,     CDCl₃): 1.70 (s, 3H), 3.79 (d, J=10.7, 1H), 3.80–3.88 (m, 1H),     4.08–4.23 (m, 2H), 4.55–4.64 (m, 1H), 4.82 (d, J=10.7; 1H), 5.30 (s     1H), 7.30 (d, J=2.6, 1H), 7.37–7.61 (m, 7H). -   b) (±)-Acetic acid     2-[(1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-yl]-ethyl     ester is prepared from acetic acid     2-(7-chloro-2-oxo-5-phenyl-2,3-dihydrobenzo[e][1,4]diazepin-1-yl)-ethyl     ester and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) according     to Example 18. LC-MS¹: t_(R)=1.13 min, [M+1]⁺=550.97. -   c)     (±)-(S*)-[(5S*)-7-Chloro-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from (±)-acetic acid     2-[(1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-yl]-ethyl     ester in analogy to Example 18. LC-MS¹: t_(R)=0.93 min,     [M+1]⁺=527.03.

Example 158

-   a)     (7-Chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-acetic     acid ethyl ester is prepared from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and bromo-acetic acid ethyl ester according to     Example 39. LC-MS¹: t_(R)=1.04 min, [M+1]⁺=357.01. -   b)     (±)-[(1S*,9bS*)-8-Chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl]-acetic     acid ethyl ester is prepared from     (7-chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-acetic     acid ethyl ester and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1)     according to Example 18. LC-MS¹: t_(R)=1.18 min, [M+1]⁺=551.02. -   c)     (±)-(S*)-((5S*)-1-Carboxymethyl-7-chloro-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is prepared from     (±)-[(1S*,9bS*)-8-Chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-hepten-5-yl]-acetic     acid ethyl ester in analogy to Example 18. LC-MS¹: t_(R)=0.94 min,     [M+1]⁺=540.99.

Example 159

(±)-(S*)-((5S*)-7-Chloro-1-ethoxycarbonylmethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic acid is isolated as a second product in Example 158. LC-MS¹: t_(R)=1.08 min, [M+1]⁺=569.03.

Example 160

-   a) Acetic acid     7-chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-ylmethyl     ester is prepared starting from     7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 39) and bromomethyl acetate in analogy to Example 39.     LC-MS¹: t_(R)=1.04 min, [M+1]⁺=343.00. -   b) (±)-Acetic acid     (1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-ylmethyl     ester is prepared from acetic acid     7-chloro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-ylmethyl     ester and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) in analogy     to Example 18. LC-MS¹: t_(R)=1.13 min, [M+1]⁺=537.01. -   c) Treating (±)-acetic acid     (1S*,9bS*)-8-chloro-1-(3,5-dimethoxy-phenoxy)-2,4-dioxo-9b-phenyl-1,3,4,9b-tetrahydro-2H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclohepten-5-ylmethyl     ester with LiOH.H₂O as described in Example 18 yields     (±)-(S)-((5S*)-7-chloro-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid. LC-MS¹: t_(R)=0.81 min, [M+1]⁺=482.97.

Example 161

A solution of (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic acid (32 mg, 64 μmol) (Example 149), N-ethyldiisopropylamine (55 μl, 320 μmol) and chlorotrimethylsilane (9 μl, 77 μmol) in dry THF (4 ml) is stirred for 1.5 h at 55° C. Acetyl chloride (7 μl, 96 μmol) is added at rt and the mixture is stirred at rt for 2 h. The solution is poured into 0.01 M aq. HCl and extracted twice with DCM. The organic phase is dried over Na₂SO₄ and evaporated. The crude product is purified by MPLC to give ethyl-diisopropyl-ammonium (±)-(1S*)-((5S*)-4-acetyl-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetate (14 mg) as a light beige solid. LC-MS²: t_(R)=4.43 min, [M+1]⁺=539.10, [M−1]⁻=537.18.

Example 162

(±)-(S*)-[(5S*)-4-Acetyl-7-chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(3,5-dimethoxy-phenoxy)-acetic acid is prepared from (±)-(S*)-[(5S*)-7-chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(3,5-dimethoxy-phenoxy)-acetic acid (Example 156) in analogy to Example 16. LC-MS¹: t_(R)=0.89 min, [M+1]⁺=675.04.

Example 163

a) (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione (Example 39) is subjected to hydrogenolysis as described in Example 18 under 6 atm of H₂ at rt for 75 min. This gives a 4:1 mixture of (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-heptene-2,4-dione and (±)-(1S*,9bS*)-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-heptene-2,4-dione which is not separated. LC-MS²: t_(R)=0.88 min, [M+1]⁺=342.91; LC-MS² (dechlorinated product): t_(R)=0.81 min, [M+1]⁺=309.00.

-   b) A mixture of     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     (150 mg, 0.44 mmol, containing 20% of     (±)-(1S*,9bS*)-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-heptene-2,4-dione),     NaH (23 mg, 55% in mineral oil, 0.57 mmol) and 2-chloropyrimidine     (65 mg, 0.57 mmol) in THF (5 ml) is strirred at rt for 1 h, then at     55° C. for 3.5 h, before it is diluted with water and sat. aq.     NaHCO₃, and extracted with EA. The organic phase is washed with     brine, dried over MgSO₄ and evaporated. The crude product is     purified by column chromatography on silica gel eluting with     heptane:EA 2:1 to furnish     (±)-(1S*,9bS*)-8-chloro-5-methyl-9b-phenyl-1-(pyrimidin-2-yloxy)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (85 mg) as a white solid. LC-MS²: t_(R)=0.98 min, [M+1]⁺=420.98. -   c) Treating     (±)-(1S*,9bS*)-8-chloro-5-methyl-9b-phenyl-1-(pyrimidin-2-yloxy)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     with LiOH.H₂O in analogy to Example 18 furnishes     (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl)-(pyrimidin-2-yloxy)-acetic     acid. LC-MS²: t_(R)=0.66 min, [M+1]⁺=438.99.

Example 164

-   a)     (±)-(1S*,9bS*)-8-Chloro-5-methyl-1-(5-methyl-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared in analogy to Example 163, starting from     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (Example 163) and 2-chloro-5-methyl-pyrimidine (prepared according     to procedures described by T. Ueda, J. J. Fox, J. Med. Chem., 6,     (1963), 697–701 and D. J. Brown, T. Nagamatsu, Aust. J. Chem., 30,     (1977), 2515–2525). LC-MS¹: t_(R)=1.03 min, [M+1]⁺=435.01. -   b) To a solution of     (±)-(1S*,9bS*)-8-chloro-5-methyl-1-(5-methyl-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (40 mg, 92 μmol) in THF (2 ml) and methanol (500 μl) is added     lithium hydroxyde monohydrate (4.6 mg, 110 μmol), dissolved in water     (1 ml). The solution is stirred for 24 h at rt. Lithium hydroxyde     monohydrate (4 mg, 95 μmol), dissolved in water (500 μl), is added     and the solution is stirred for 6 h at rt. The solution is diluted     with water and the organic solvents are evaporated in vacuo. The     solution is acidified to pH 6 and the mixture is lyophilized. The     residue is purified by prep. HPLC to give     (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(5-methyl-pyrimidin-2-yloxy)-acetic     acid (13 mg) as a white powder. LC-MS¹: t_(R)=0.89 min,     [M+1]⁺=452.98.

Example 165

-   a)     (±)-(1S*,9bS*)-8-Chloro-1-(5-methoxy-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared in analogy to Example 163, starting from     8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     (Example 163) and 2-methanesulfonyl-5-methoxy-pyrimidine (prepared     according to procedures described by H. C. Koppel, R. H.     Springer, R. K. Robins, C. C. Cheng, J. Org. Chem., 27, (1962),     3614–3617 and E. Merifield, E. J. Thomas, J. Chem. Soc., Perkin     Trans I, (1999), 3269–3283). LC-MS¹: t_(R)=1.01 min, [M+1]⁺=450.98. -   b)     (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(5-methoxy-pyrimidin-2-yloxy)-acetic     acid (44 mg) is obtained by treating     (±)-(1S*,9bS*)-8-chloro-1-(5-methoxy-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (110 mg, 244 μmol) with LiOH.H₂O as described in Example 164.     LC-MS¹: t_(R)=0.89 min, [M+1]⁺=468.97.

Example 166

(±)-(1S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 163 starting from (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 163) and 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8). LC-MS¹: t_(R)=0.96 min, [M+1]⁺=498.99.

Example 167

-   a)     (±)-(1S*,9bS*)-1-Benzyloxy-8-chloro-5-(3,5-dimethoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is obtained from     7-chloro-1-(3,5-dimethoxy-benzyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 156) and benzyloxy-acetic acid (Example 18) according to     Example 18. LC-MS¹: t_(R)=1.25 min, [M+1]⁺=569.02. -   b) A suspension of     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-5-(3,5-dimethoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     (540 mg, 949 μmol), 10% Pd on charcoal (100 mg) and acetic acid (217     μl, 3.79 mmol) in THF (10 ml) and ethanol (10 ml) is stirred for 40     min at rt under 6 atm of hydrogen. 10% Pd on charcoal (100 mg) is     added and the suspension is stirred for 2 h at rt under 6 atm of     hydrogen. Acetic acid (435 μl, 7.61 mmol) is added and the     suspension is stirred for 2.5 h at rt under 6 atm of hydrogen. 10%     Pd on charcoal (100 mg) is added and the suspension is stirred for     18 h at rt under 6 atm of hydrogen. 10% Pd on charcoal (100 mg) is     added and the suspension is stirred for 6 h at rt under 7.5 atm of     hydrogen. The suspension is filtered through celite and the filtrate     is evaporated in vacuo. The crude product is purified by column     chromatography (silicagel, heptane/EA 2:1 to 1:2) to give     (±)-(1S*,9bS*)-8-chloro-5-(3,5-dimethoxy-benzyl)-1-hydroxy-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (248 mg) as a white solid. LC-MS¹: t_(R)=1.03 min, [M+1]⁺=479.02. -   c)     (±)-(1S*,9bS*)-8-Chloro-5-(3,5-dimethoxy-benzyl)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is synthesized from     (±)-(1S*,9bS*)-8-chloro-5-(3,5-dimethoxy-benzyl)-1-hydroxy-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     and 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8) in     analogy to Example 18. LC-MS¹: t_(R)=1.24 min, [M+1]⁺=617.01. -   d)     (±)-(1S*)-[(5S*)-7-Chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid is prepared from     (±)-(1S*,9bS*)-8-chloro-5-(3,5-dimethoxy-benzyl)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     in analogy to Example 147. LC-MS¹: t_(R)=1.07 min, [M+1]⁺=635.05.

Example 168

(±)-(1S*)-((5S*)-4-Acetyl-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 16, starting from of (±)-(1S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid (Example 166). LC-MS¹: t_(R)=0.73 min, [M+1]⁺=541.03.

Example 169

(±)-(S*)-(5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid methyl ester is prepared in analogy to Example 131. LC-MS¹: t_(R)=0.94 min, [M+1]⁺=513.01.

Example 170

(±)-(1S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 163, starting from (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cyclo-heptene-2,4-dione (Example 163) and 2-methanesulfonyl-4,6-dimethyl-pyrimidine (Example 19). LC-MS¹: t_(R)=0.67 min, [M+1]⁺=467.01.

Example 171

-   a)     (±)-(1S*,9bS*)-1-Benzyloxy-8-chloro-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared starting from     7-chloro-1-(4-methoxy-benzyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (prepared in analogy to Example 39) and benzyloxyacetyl chloride in     analogy to Example 27. LC-MS¹: t_(R)=1.26 min, [M+1]⁺=539.03. -   b) A suspension of Pd/C (400 mg, 10% Pd) in THF (5 ml) is added to a     solution of     (±)-(1S*,9bS*)-1-benzyloxy-8-chloro-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     (5.0 g, 9.28 mmol) in THF (25 ml), ethanol (25 ml) and     1,2-dichlorobenzene (30 ml). The mixture is stirred at rt under 1     atm H₂ for 165 min before the catalyst is filtered off. The filtrate     is partially evaporated and the product precipitates from the     remaining 1,2-dichlorobenzene. The product is collected, washed with     diethyl ether and dried to give     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (4.03 g) as a white powder. No dechlorination is observed. LC-MS¹:     t_(R)=1.03 min, [M+1]⁺=448.99. -   c)     (±)-(1S*,9bS*)-8-chloro-1-hydroxy-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is reacted with 2-methanesulfonyl-4,6-dimethyl-pyrimidine     (Example 19) as described in Example 25 to give     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione.     LC-MS¹: t_(R)=1.20 min, [M+1]⁺=555.04. -   d)     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is treated with LiOH.H₂O as described in Example 25 to furnish     (±)-(S*)-[(5S*)-7-chloro-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid. LC-MS¹: t_(R)=1.09 min, [M+1]⁺=573.07.

Example 172

-   a)     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     (Example 171) is treated with ammonium cerium(IV)nitrate as     described in Example 48 to furnish     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione.     LC-MS¹: t_(R)=0.99 min, [M+1]⁺=435.03. -   b) In analogy to Example 48,     (±)-(S*)-[(5S*)-1-(4-butylbenzyl)-7-chloro-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid is obtained starting from     (±)-(1S*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     and 4-butylbenzyl bromide (prepared from 4-butylbenzylalcohol).     LC-MS¹: t_(R)=1.32 min, [M+1]⁺=599.14.

Example 173 to 178

In analogy to Example 172 the following compounds are prepared:

t_(R) (LC-MS¹) Example R [min] [M + 1]⁺ 173

1.12 597.05 174

1.14 597.06 175

1.15 611.01 176

1.10 597.05 177

1.14 597.03 178

1.13 597.02

Example 179

(±)-(S*)-((5S*)-7-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-diethyl-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Examples 29 and 163. LC-MS¹: t_(R)=1.01 min, [M+1]⁺=495.06.

Example 180

(±)-(S*)-(3,5-Dimethoxy-phenoxy)-[(5S*)-5-(2-fluoro-phenyl)-1-methyl-7-nitro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared starting from flunitrazepam (5-(2-fluoro-phenyl)-1-methyl-7-nitro-1,3-dihydro-benzo[e][1,4]diazepin-2-one) and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) in analogy to Example 18. LC-MS¹: t_(R)=0.82 min, [M+1]⁺=526.02.

Example 181

-   a) A solution of 2-amino-4,5-dimethoxybenzonitrile (8.0 g, 45 mmol)     in THF (50 ml) is added dropwise at 5° C. to a solution of phenyl     magnesiumbromide (45 ml 3 M in diethyl ether, 135 mmol) in THF (100     ml). The resulting orange brown solution is stirred at rt for 1 h,     at 55° C. for 2.5 h before the reaction is quenched at 0° C. with 2     N aq. HCl. The mixture is stirred at acidic pH, then neutralized     with aq. NaOH. The organic phase is separated, the aq. phase is     extracted three times with EA. The combined organic phase is washed     with brine, dried over MgSO₄ and evaporated to give     2-(imino-phenyl-methyl)-4,5-dimethoxy-phenylamine (12.0 g) as a     brown oil. LC-MS¹: t_(R)=1.10 min, [M+1]⁺=257.10. -   b) (In analogy to a procedure described by L. Berger, L. H.     Sternbach, in U.S. Pat. No. 3,268,586) A solution of     2-(imino-phenyl-methyl)-4,5-dimethoxy-phenylamine (2.0 g, 7.77 mol)     and glycine ethyl ester hydrochloride (1.74 g, 12.4 mmol) in     pyridine (50 ml) is stirred at reflux for 8 h before it is     evaporated. Remaining pyridine is coevaporated with toluene. The     product is crystallised from methanol at 0° C. The material is     collected and dried to give     7,8-dimethoxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (1.35 g) as a beige powder. LC-MS¹: t_(R)=0.71 min, [M+1]⁺=297.04. -   c) 7,8-Dimethoxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one is     methylated as described in Example 39 to give     7,8-dimethoxy-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     as a yellow foam. ¹H-NMR (300 MHz, CDCl₃): 3.39 (s, 3H), 3.74 (s,     3H), 3.79 (d, J=10.5, 1H), 3.97 (s, 3H), 4.79 (d, J=10.5, 1H), 6.69     (s, 1H), 6.77 (s, 1H), 7.36–7.46 (m, 3H), 7.62–7.68 (m, 2H). LC-MS¹:     t_(R)=0.73 min, [M+1]⁺=311.04. -   d)     (±)-(S*)-((5S*)-7,8-Dimethoxy-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic     acid is obtained in analogy to Example 18. LC-MS¹: t_(R)=0.77 min,     [M+1]⁺=523.10.

Example 182

(±)-(S*)-((5S*)-8-Chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(3,5-dimethoxy-phenoxy)-acetic acid is prepared in analogy to Example 181. LC-MS¹: t_(R)=0.91 min, [M+1]⁺=497.02.

Example 183

-   a) 4-Methoxy-2-nitro-benzonitrile is obtained from     4-methoxy-2-nitro-phenylamine according to procedures described     by J. Qiu, S. H. Stevenson, M. J. O'Beirne, R. B. Silverman, J. Med.     Chem., 42, (1999), 329–332. -   b) A suspension of 4-methoxy-2-nitro-benzonitrile (7.24 g, 40.6     mmol) and 10% Pd on charcoal (724 mg) in dry ethanol (100 ml) is     stirred for 2 h under an atmosphere of hydrogen gas (balloon). The     mixture is filtered through celite and the filtrate evaporated. The     crude product is purified by column chromatography (silica gel,     heptane/EA 3:1) to give 2-amino-4-methoxy-benzonitrile (1.8 g) as a     green powder. LC-MS²: t_(R)=3.43 min, [M+1]⁺=149.02. -   c) A 3 M solution of phenyl magnesium bromide in diethylether (18.9     ml, 56.7 mmol) is diluted with dry THF (30 ml) and cooled to 0° C.     2-Amino-4-methoxy-benzonitrile (2.8 g, 18.9 mmol), dissolved in dry     THF (20 ml), is added. The suspension is stirred for 30 min at 0°     C., then for 2 h at rt and for 18 h at 40° C. The mixture is     acidified with 2 M aq. HCl, then basified with 2 M aq NaOH. The     aqueous phase is extracted three times with diethylether. The     organic phase is washed with sat. aq. NaCl, dried over MgSO₄ and     evaporated to give (2-amino-4-methoxy-phenyl)-phenyl-methanone     (3.2 g) as an orange-brown oil. LC-MS¹: t_(R)=0.73 min,     [M+1]⁺=227.12. -   d) 8-methoxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one is     obtained from (2-amino-4-methoxy-phenyl)-phenyl-methanone and     glycine methyl ester hydrochloride in analogy to procedures     described by H. Umemiya, H. Fukasawa, M. Ebisawa, L. Eyrolles, E.     Kawachi, G. Eisenmann, H. Gronemeyer, Y. Hashimoto, K. Shudo, H.     Kagechika, J. Med. Chem., 40, (1997), 4222–4234. LC-MS¹: t_(R)=0.73     min, [M+1]⁺=267.00. -   e) To a solution of     8-methoxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (1 g,     3.76 mmol) in dry DMF (25 ml) is slowly added NaH (60% in mineral     oil) (180 mg, 4.50 mmol) at 0° C. The suspension is stirred at 0° C.     and allowed to slowly warm to rt. Stirring is continued for 16 h.     The mixture is again cooled to 0° C. and iodomethane (258 μl, 4.13     mmol), dissolved in dry DMF (5 ml), is added. The suspension is     stirred for 30 min at rt. Iodomethane (65 μl, 1.04 mmol), dissolved     in dry DMF (2 ml), is added and the mixture stirred for 30 min at     rt. The solution is poured into water. The aqueous phase is     extracted three times with EA. The organic phase is dried over MgSO₄     and evaporated to give     8-methoxy-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (1 g) as a yellow thick oil. LC-MS¹: t_(R)=0.75 min, [M+1]⁺=281.07. -   f)     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared from     8-methoxy-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1b)) as described     in Example 18. LC-MS¹: t_(R)=1.07 min, [M+1]⁺=475.06. -   g)     (±)-(S*)-(3,5-Dimethoxy-phenoxy)-((5S*)-8-methoxy-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid is prepared from     (±)-(1S*,9bS*)-1-(3,5-dimethoxy-phenoxy)-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     in analogy to Example 18. LC-MS¹: t_(R)=0.94 min, [M+1]⁺=493.09.

Example 184

-   a)     (±)-(1S*,9bS*)-1-Benzyloxy-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is obtained from     8-methoxy-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (Example 183) and benzyloxyacetic acid (Example 18) in analogy to     Example 18. LC-MS¹: t_(R)=1.09 min, [M+1]⁺=429.09. -   b) A suspension of     (±)-(1S*,9bS*)-1-benzyloxy-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (638 mg, 1.49 mmol), 10% Pd on charcoal (100 mg) and acetic acid     (340 μl, 5.95 mmol) in THF (10 ml) and ethanol (6 ml) is stirred for     30 min at rt under 6 atm of hydrogen. 10% Pd on charcoal (100 mg) is     added and the mixture is stirred for 16 h at rt under 6 atm of     hydrogen. The suspension is filtered through celite and the filtrate     evaporated to give     (±)-(1S*,9bS*)-1-hydroxy-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (557 mg) as a light grey oil. LC-MS¹: t_(R)=0.83 min, [M+1]⁺=338.99. -   c)     (±)-(1S*,9bS*)-1-(4,6-Dimethoxy-pyrimidin-2-yloxy)-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is obtained from     (±)-(1S*,9bS*)-1-hydroxy-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     and 2-methanesulfonyl-4,6-dimethoxy-pyrimidine (Example 8) in     analogy to Example 18. LC-MS¹: t_(R)=1.06 min, [M+1]⁺=477.05. -   d)     (±)-(S*)-(4,6-Dimethoxy-pyrimidin-2-yloxy)-((5S*)-8-methoxy-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic     acid is prepared from     (±)-(1S*,9bS*)-1-(4,6-dimethoxy-pyrimidin-2-yloxy)-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     in analogy to Example 18.

LC-MS¹: t_(R)=0.88 min, [M+1]⁺=494.99.

Example 185

-   a)     7-Chloro-5-(2-fluoro-phenyl)-1-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared in analogy to Example 39. LC-MS²: t_(R)=4.29 min,     [M+1]⁺=303.11. -   b)     (±)-(1S*,9bS*)-1-Benzyloxy-8-chloro-9b-(2-fluoro-phenyl)-5-methyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     is prepared in analogy to Example 25. LC-MS²: t_(R)=4.97 min,     [M+1]⁺=451.24. -   c) Hydrogenolysis of     (±)-(1S*,9bS*)-1-Benzyloxy-8-chloro-9b-(2-fluoro-phenyl)-5-methyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione     as described in Example 25 gives     (±)-(1S*,9bS*)-9b-(2-fluoro-phenyl)-1-hydroxy-5-methyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione.     LC-MS²: t_(R)=3.33 min, [M+1]⁺=327.17. -   d) The introduction of the 4,6-dimethylpyrimidine and the β-lactam     cleavage are carried out as described in Example 25 to give     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(2-fluoro-phenyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid. LC-MS²: t_(R)=3.56 min, [M+1]⁺=451.20, [M−1]⁻=449.21.

Example 186

(±)-(S*)-(4,6-Dimethoxy-pyrimidin-2-yloxy)-[(5S*)-5-(2-fluoro-phenyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to the procedures given in Example 185. LC-MS²: t_(R)=3.80 min, [M+1]⁺=483.24, [M−1]⁻=481.20.

Example 187

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-methyl-2-oxo-5-m-tolyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is obtained as a light yellow powder starting from (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-m-tolyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 188), following the procedures described in Example 191. ¹H-NMR (300 MHz, CDCl₃): 2.07 (s, 3H), 2.14 (s, 6H), 2.25 (s, 3H), 3.49 (s, 2H), 6.36 (s, 1H), 6.46 (s, 1H), 6.6–6.9 (m, 4H), 7.06 (dd, J=1.2, 7.6, 1H), 7.33 (t, J=7.02, 1H), 7.4 (td, J_(d)=1.2, J_(t)=7.6, 1H), 7.8 (m, 1H). LC-MS¹: t_(R)=0.84 min, [M+1]⁺=447.

Example 188

-   a) Toluene-3-magnesium bromide is prepared under Grignard conditions     from magnesium turnings (2.67 g, 0.110 mol) and 3-bromo toluene (10     ml, 82.4 mmol) in anhydrous diethyl ether (45 ml). After refluxing     the reaction mixture for 1 h, it is cooled to rt. A solution of     2-aminobenzo nitrile (3.24 g, 27.5 mmol) in diethylether (25 ml) is     added dropwise. Upon completion of the addition, the Grignard     solution is heated to reflux for 1 h, then cooled to rt. To the     reaction mixture is added ice and the Grignard complex is decomposed     with HCl conc. (25 ml), the solution is stirred at RT over 30 min,     cooled to RT and rendered alkaline with 10% NaOH. The layers are     separated, the aq. phase is extracted with diethylether (2×), the     combined organic phases are washed with brine, dried over MgSO₄ and     the solvent removed in vacuo to yield     2-(imino-m-tolyl-methyl)-phenylamine (5 g), which is not further     purified. LC-MS¹: t_(R)=0.67 min, [M+1]⁺=211. -   b) 2-(imino-m-tolyl-methyl)-phenylamine (4.28 g, 20.3 mmol) and     glycine ethylester hydrochloride (4.52 g, 32.4 mmol) are dissolved     in abs. pyridine (70 ml) and heated to reflux over 15 h. Upon     completion of the reaction, the solvent is removed in vacuo with     toluene. The crude residue is purified by column chromatography on     silica (0%–50% EA in DCM) to give     5-m-tolyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (1.0 g) as an     orange foam.

¹H-NMR (300 MHz, CDCl₃): 2.36 (s, 3H), 4.32 (s, 2H), 7.11–7.18 (m, 3H), 7.25 (d, J=1.3, 3H), 7.35 (dd, J=1.4, 7, 1H), 7.41 (s, 1H), 7.5 (m, 1H), 9.20 (s, 1H). LC-MS¹: t_(R)=0.68 min, [M+1]⁺=251.

The the [2+2]-cycloaddition, the hydrogenation, the introduction of the 4,6-dimethyl pyrimidine moiety and the β-lactam cleavage are carried out as described in the procedures given in Example 192 to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy benzyl)-2-oxo-5-m-tolyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid. ¹H-NMR 300 MHz, CDCl₃): 2.13 (s, 3H), 2.23 (s, 6H), 2.80 (d, J=14.6, 1H), 3.58 (m, 2H), 3.75 (s, 3H), 4.14 (d, J=14.6, 1H), 6.45 (s, 2H), 6.77 (d, J=8.8, 4H), 6.92 (d, J=7.6, 2H), 7.02 (d, J=8.8, 2H), 7.23–7.35 (m, 2H), 7.78 (m, 1H). LC-MS¹: t_(R)=1.01 min, [M+1]⁺=553.

Example 189

(±)-(S*)-[(5S*)-5-(3,5-Dimethyl-phenyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is obtained as a light yellow powder starting from (±)-(1S*,9bS*)-9b-(3,5-dimethyl-phenyl)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 190), following the procedures described in Example 191. ¹H-NMR (300 MHz, CDCl₃): 2.09 (s, 6H), 2.22 (s, 6H), 2.35 (s, 3H), 3.57 (s, 2H), 6.44 (s, 1H), 6.50 (s, 1H), 6.57 (s, 1H), 7.14 (dd, J=1.7, 7.9, 1H), 7.21 (m, 1H), 7.36–7.53 (m, 3H), 7.83 (m, 1H). LC-MS¹: t_(R)=0.87 min, [M+1]⁺=461.

Example 190

(±)-(S*)-[(5S*)-5-(3,5-Dimethyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared as described in Example 192. ¹H-NMR (300 MHz, CDCl₃): 2.12 (s, 6H), 2.23 (s, 6H), 2.77 (d, J=15.2, 1H), 3.64 (s, 2H), 3.77 (s, 3H), 4.24 (d, J=15.2, 1H), 6.44 (s, 1H), 6.53 (s, 1H), 6.60 (s, 1H), 6.78 (d, J=8.2, 2H), 6.95 (dd, J=1.2, 7.6, 1H), 7.02 (d, J=8.2, 2H), 7.32 (t, J=7.6, 1H) 7.40 (t, J=7.6, 1H), 7.83 (d, J=7.6, 1H). LC-MS¹: t_(R)=1.04 min, [M+1]⁺=567.

Example 191

(±)-(1S*,9bS*)-1-(4,6-Dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-(3-trifluoromethylphenyl)-5,9b-dihydro-1H-2a,5-diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione is prepared as described in Example 192.

-   a) An aqueous solution of cerium ammonium nitrate (10.48 g, 19.1     mmol in 33 ml H₂O) is added dropwise to a cooled (0° C.) solution of     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-(3-trifluoromethylphenyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (3.75 g, 6.4 mmol) in acetonitrile (87 ml). The reaction mixture is     stirred at 0° C. for 1 h, followed by 4 h at rt, diluted with DCM     and the layers are separated. The aq. phase is extracted with DCM     (2×), the combined organic phases are washed with brine, dried over     MgSO₄ and the solvent removed in vacuo. The crude product is     precipitated from diethylether to yield     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (2.33 g) as a white powder. LC-MS¹: t_(R)=0.99 min, [M+1]⁺=469. -   b) Methyliodide (0.692 ml, 7.5 mmol) is added to a suspension of     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (2.33 g, 5 mmol) and potassium carbonate (2.07 g, 15 mmol) in DMF     (50 ml). The reaction is heated to 60° C. for 15 h, then partitioned     between water and DCM. The layers are separated, the aq. layer is     extracted with DCM (2×), the combined organic extracts are washed     with brine, dried over MgSO₄ and the solvent removed in vacuo to     give     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-methyl-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (1.7 g), which is not further purified. LC-MS¹: t_(R)=1.05 min,     [M+1]⁺=483. -   c) An aqueous solution of LiOH.H₂O (0.177 g, 4.2 mmol in 2 ml water)     is added to a solution of     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-methyl-9b-(3-trifluoromethyl-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (1.7 g, 3.5 mmol) in THF (8 ml) and methanol (3 ml). Stirring is     continued for 1 h, the pH adjusted to 5 with 1 N HCl and the     reaction mixture is diluted with DCM. The layers are separated, the     organic phase is washed with brine, dried over MgSO₄ and the solvent     removed in vacuo. The crude product is purified by HPLC on Rp-C₁₈     silica gel to afford     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-methyl-2-oxo-5-(3-trifluoromethyl-phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid (0.02 g) as a white powder. ¹H-NMR (300 MHz, CDCl₃): 2.21 (s,     6H), 2.33 (s, 3H), 3.63 (d, J=14.7, 1H), 3.56 (d, J=13.5, 1H), 6.46     (s, 1H), 6.53 (s, 1H), 7.16–7.57 (m, 7H), 7.83 (m, 1H). LC-MS¹:     t_(R)=0.93 min, [M+1]⁺=501.

Example 192

-   a) 3-(Trifluoromethyl)benzyl-1-magnesium bromide is prepared under     Grignard conditions from magnesium turnings (4.22 g, 0.173 mol) and     1-bromo-3-(trifluoromethyl)benzene (17.5 ml, 127 mmol) in anhydrous     diethyl ether (65 ml). After refluxing the reaction mixture for 4 h,     it is cooled to rt. A solution of 2-aminobenzo nitrile (5 g, 42.3     mmol) in diethylether (35 ml) is added dropwise. Upon completion of     the addition, the Grignard solution is heated to reflux over 4 h,     then cooled to rt. The Grignard complex is decomposed with 2M HCl     mixed with ice, the solution is refluxed over 2 h, cooled to RT and     rendered alkaline with 10% NaOH. The layers are separated, the aq.     phase is extracted with diethylether, the combined organic phases     are washed with brine, dried over MgSO₄ and the solvent removed in     vacuo to yield 2-amino-3′-(trifluoromethyl)benzophenone (11.72 g) as     a light yellow powder, which is not further purified. LC-MS¹:     t_(R)=1.14 min, [M+1]⁺=266. -   b) 2-Amino-3′-(trifluoromethyl) benzophenone (11.72 g, 44.2 mmol) is     dissolved in abs. pyridine (250 ml), glycine ethylester     hydrochloride (9.9 g, 70.7 mmol) is added and the reaction mixture     heated to reflux over 72 h. Upon completion of the reaction, the     solvent is removed in vacuo with toluene. The reaction mixture is     partitioned between water and EA, the layers are separated, the aq.     phase is extracted once again with EA and the combined organic     phases are washed with brine, dried over MgSO₄ and the solvent     removed in vacuo. The residue is purified over silica (0% –70% EA in     heptane) to yield     5-(3-trifluoromethylphenyl)-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (4.96 g) as an orange powder. LC-MS¹: t_(R)=0.92 min, [M+1]⁺=305. -   c) 4-Methoxy benzyl chloride (2.32 ml, 17.1 mmol) is added to a     suspension of 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (4.96     g, 16.3 mmol) and potassium carbonate (6.76 g, 48.9 mmol) in DMF     (100 ml). The suspension is stirred at rt over 15 h, diluted with EA     and extracted with water. The aq. phase is extracted with EA (2×),     the combined organic layers are washed with brine, dried over MgSO₄     and the solvent removed in vacuo. The crude residue is precipitated     from diethylether to afford     1-(4-methoxy-benzyl)-5-(3-trifluoromethylphenyl)-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (6.35 g) as a white crystalline powder. ¹H-NMR (300 MHz, CDCl₃):     3.68 (s, 3H), 3.87 (d, J=10.5, 1H), 4.65 (d, J=14.6, 1H), 4.89 (d,     J=14.6, 1H), 5.63 (d, J=14.6, 1H), 6.62 (d, J=8.8, 2H), 6.93 (d,     J=8.8, 2H), 7.11 (m, 2H), 7.42–7.56 (m, 4H), 7.63–7.7 (m, 2H).     LC-MS¹: t_(R)=1.14 min, [M+1]⁺=425. -   d)     1-(4-Methoxy-benzyl)-5-(3-trifluoromethylphenyl)-1,3-dihydro-benzo[e][1,4]diazepin-2-one     (6.33 g, 14.9 mmol) is dissolved in DCM (65 ml), cooled to 0° C.,     benzyloxy acetylchloride (3 ml, 19.4 mmol) is added, followed by     triethylamine (6.2 ml, 44.7 mmol). The ice bath is let expire over     15 h. The reaction mixture is partitioned between sat. aq. NaHCO₃     and EA, the layers are separated. The aq. phase is extracted with EA     (2×), the combined organic phases are washed with brine, dried over     MgSO₄ and the solvent removed in vacuo. The crude product is     suspended in diethylether to give     (±)-(1S*,9bS*)-1-benzyloxy-5-(4-methoxy-benzyl)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5-diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione     (6.73 g) as a white powder. ¹H-NMR (300 MHz, CDCl₃): 3.33 (d,     J=15.2, 1H), 3.76 (s, 3H), 3.83 (d, J=13.5, 1H), 4.51–4.55 (m, 4H),     5.26 (s, 1H), 6.71 (d, J=8.8, 2H), 6.92 (d, J=8.8, 2H), 6.99–7.06     (m, 3H), 7.23–7.36 (m, 6H), 7.5–7.6 (m, 2H). LC-MS¹: t_(R)=1.22 min,     [M+1]⁺=573. -   e) To Pd/C (1.5 g, 10%) are added     (±)-(1S*,9bS*)-1-benzyloxy-5-(4-methoxy-benzyl)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (6.73 g, 11.8 mmol), THF (70 ml), ethanol (20 ml) and acetic acid     (1.5 ml). The reaction mixture is stirred at 50° C. under 7 atm H₂     for 14 h. The Pd-catalyst is filtered and the solvent removed in     vacuo to afford     (±)-(1S*,9bS*)-1-hydroxy-5-(4-methoxy-benzyl)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione     (5.67 g) as a white crystalline foam, which is used without further     purification. LC-MS¹: t_(R)=1.03 min, [M+1]⁺=483. -   f) Potassium carbonate (4.89 g, 35.4 mmol) is added to a solution of     (±)-(1S*,9bS*)-1-hydroxy-5-(4-methoxy-benzyl)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione     (5.67 g, 11.8 mmol) and 2-methanesulfonyl-4,6-dimethyl-pyrimidine     (2.63 g, 14.1 mmol, Example 19) in DMF (60 ml). The resulting     suspension is heated to 50° C. over 48 h, diluted with DCM, washed     with water (2×), brine (2×), dried over MgSO₄ and the solvent     removed in vacuo. The crude product is suspended in diethylether to     yield     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-(3-trifluoromethylphenyl)-5,9b-dihydro-1H-2a,5-diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione     (4.06 g) as a white powder. LC-MS¹: t_(R)=1.17 min, [M+1]⁺=589. -   g) An aqueous solution of LiOH.H₂O (0.026 g, 0.61 mmol in 1 ml     water) is added to a solution of     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-(3-trifluoromethyl-phenyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.3 g, 0.51 mmol) in THF (3 ml) and methanol (1 ml). The mixture is     stirred at rt for 2 h, the pH is adjusted to pH=5 with 1 N HCl and     the solvents removed in vacuo. The crude product is purified by     prep. tlc on silica (MeOH:CH₂Cl₂=2:8) to afford     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-(3-trifluoromethyl-phenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid (0.1 g) as a white powder. ¹H-NMR (300 MHz, CDCl₃): 2.25 (s,     6H), 2.78 (d, J=15.8, 1H), 3.5 (m, 1H), 3.61 (m, 1H), 3.74 (s, 3H),     4.06 (d, J=14.7, 1H), 6.37 (s, 1H), 6.52 (s, 1H), 6.76 (d, J=8.2,     2H), 6.93–7.54 (m, 8H), 7.76 (m, 1H). LC-MS¹: t_(R)=1.09 min,     [M+1]⁺=607.

Example 193

-   a) (2-Amino-phenyl)-(3-ethyl-phenyl)-methanone is prepared starting     from 2-aminobenzonitrile and 1-bromo-3-ethylbenzene in analogy to     Example 192. LC-MS²: t_(R)=5.21 min, [M+1]⁺=226.08. -   b)     5-(3-Ethyl-phenyl)-1-(4-methoxy-benzyl)-1,3-dihydro-benzo[e][1,4]di-azepin-2-one     is prepared in analogy to Example 39. LC-MS¹: t_(R)=0.99 min,     [M+1]⁺=385.02. -   c)     (±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid is prepared in analogy to Example 192. LC-MS¹: t_(R)=1.06 min,     [M+1]⁺=567.09.

Examples 194 to 200

The following examples are prepared starting from (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-(3-ethyl-phenyl)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 193) in analogy to the procedures given in Example 48:

t_(R) (LC-MS¹) Example R [min] [M + 1]⁺ 194

1.08 591.08 195

1.26 579.15 196

1.13 591.11 197

1.10 591.11 198

1.30 593.19 199

1.07 573.11 200

1.12 591.10

Example 201

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-methoxy-phenyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Example 191. LC-MS¹: t_(R)=0.83 min, [M+1]⁺=463.15.

Example 202

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-5-(3-methoxy-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared in analogy to Example 192. LC-MS¹: t_(R)=0.99 min, [M+1]⁺=569.08.

Examples 203 to 207

The following examples are prepared starting from (±)-(1S*,9bS*)-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-(3-methoxy-phenyl)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 202) in analogy to the procedures given in Example 48:

t_(R) (LC-MS¹) Example R [min] [M + 1]⁺ 203

1.01 593.01 204

0.79 506.99 205

1.01 593.04 206

1.16 581.13 207

1.05 593.11

Example 208

-   a) (2-Amino-phenyl)-biphenyl-3-yl-methanone is prepared starting     from 2-aminobenzonitrile and 3-bromobiphenyl in analogy to     Example 192. LC-MS²: t_(R)=5.32 min, [M+1]⁺=274.11. -   b) 5-Biphenyl-3-yl-1-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is prepared in analogy to Example 39. LC-MS²: t_(R)=4.61 min,     [M+1]⁺=327.27. -   c)     (±)-(S*)-((5S*)-5-Biphenyl-3-yl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic     acid is prepared in analogy to Example 192. LC-MS²: t_(R)=4.39 min,     [M+1]⁺=541.41, [M−1]⁻=539.20.

Example 209

(±)-(S*)-((5S*)-5-Biphenyl-3-yl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 208. LC-MS²: t_(R)=4.17 min, [M+1]⁺=509.20, [M−1]⁻=507.21.

Example 210

(±)-(S*)-[(5S*)-5-Biphenyl-3-yl-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared in analogy to Example 193. LC-MS¹: t_(R)=1.13 min, [M+1]⁺=615.14.

Example 211 to 213

The following examples are prepared starting from (±)-(1S*,9bS*)-9b-biphenyl-3-yl-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 210) in analogy to the procedures given in Example 48:

t_(R) (LC-MS¹) Example R [min] [M + 1]⁺ 211

1.15 639.02 212

0.89 553.02 213

1.13 639.04

Example 214

(±)-(S*)-[(5S*)-5-Biphenyl-3-yl-4-methyl-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid is prepared starting from (±)-(S*)-[(5S*)-5-biphenyl-3-yl-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (Example 211) in analogy to Example 127. LC-MS¹: t_(R)=1.17 min, [M+1]⁺=653.08.

Example 215

(±)-(S*)-(4,6-Dimethoxy-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-p-tolyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid is prepared in analogy to Example 39 and 27 starting from (2-amino-phenyl)-p-tolyl-methanone. LC-MS²: t_(R)=3.84 min, [M+1]⁺=479.40, [M−1]⁻=477.27.

Example 216

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-p-tolyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid is prepared in analogy to Example 39 and 27 starting from (2-amino-phenyl)-p-tolyl-methanone. LC-MS²: t_(R)=3.67 min, [M+1]⁺=447.43, [M−1]⁻=445.24.

Example 217

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(4-fluoro-3-methyl-phenyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is obtained as a light yellow powder starting from (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-(4-fluoro-3-methyl-phenyl)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione (Example 218) following procedures described in Example 191. ¹H-NMR (300 MHz, CDCl₃): 2.05 (s, 3H), 2.22 (s, 6H), 2.40 (s, 3H), 3.47 (d, J=13.4, 1H), 3.54 (d, J=12.3, 1H), 6.37 (s, 1H), 6.49 (s, 1H), 6.68 (t, J=8.2, 1H), 6.83–6.96 (m, 2H), 7.12 (d, J=7.6, 1H), 7.36 (t, J=7.6, 1H), 7.4 (t, J=7.6, 1H), 7.77 (m, 2H). LC-MS¹: t_(R)=0.86 min, [M+1]⁺=465.

Example 218

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(4-fluoro-3-methyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared as described in Example 192, by reacting 5-bromo-2-fluoro-toluene under Grignard conditions with 2-amino benzonitrile and ring cyclization to the corresponding benzodiazepinone intermediate.

-   a)     5-(4-Fluoro-3-methyl-phenyl)-1,3-dihydro-benzo[e][1,4]diazepin-2-one     is obtained as a brown powder. ¹H-NMR (300 MHz, CDCl₃): 2.28 (s,     3H), 4.29 (s, 2H), 6.98 (t, J=8.8, 1H), 7.13–7.2 (m, 2H), 7.24–7.33     (m, 2H), 7.44–7.53 (m, 2H), 9.33 (s, 1H). LC-MS¹: t_(R)=0.70 min,     [M+1]⁺=269. -   b) The     (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(4-fluoro-3-methyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid is obtained from the alkaline hydrolysis of     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-9b-(4-fluoro-3-methyl-phenyl)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.213 g, 0.419 mmol) as a white solid (0.071 g), after purification     by prep. tlc on silica (DCM:MeOH=9:1). ¹H-NMR (300 MHz, CDCl₃): 1.98     (s, 3H), 2.16 (s, 6H), 2.84 (d, J=15.8, 1H), 3.51 (m, 2H), 3.69 (s,     3H), 4.17 (d, J=14.6, 1H), 6.32 (s, 1H), 6.42 (s, 1H), 6.61 (m, 1H),     6.70 (d, J=8.8, 2H), 6.98–7.0 (m, 5H), 7.24 (m, 2H), 7.72 (m, 1H).     LC-MS¹: t_(R)=1.02 min, [M+1]⁺=571.

Example 219

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(4-fluoro-3-methyl-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared starting from (±)-(1S*,9bS*)-1-(4,6-Dimethyl-pyrimidin-2-yloxy)-9b-(4-fluoro-3-methyl-phenyl)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cyclo-heptene-2,4-dione (Example 218) in analogy to Example 48. LC-MS¹: t_(R)=1.04 min, [M+1]⁺=595.08.

Example 220

(±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-pentyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is obtained as described in Example 193, by reacting 1-bromo pentane under Grignard conditions with 2-amino benzonitrile and ring cyclization to the corresponding benzodiazepinone intermediate.

-   a) 5-Pentyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one is isolated as     an orange viscous oil. ¹H-NMR (300 MHz, CDCl₃): 0.82 (t, J=7.0, 3H),     1.24 (m, 4H), 1.56 (m, 2H), 2.76 (t, J=7.6, 2H), 4.10 (s, 2H), 7.42     (dt, J_(d)=1.5, J_(t)=7.0, 1H), 7.53 (d, J=7.6, 1H), 9.61 (s, 1H).     LC-MS¹: t_(R)=0.74 min, [M+1]⁺=231. -   b)     (±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-pentyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic     acid is obtained from the alkaline hydrolysis of     (±)-(1S*,9bS*)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-pentyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione     (0.5 g, 0.97 mmol) as a white powder (0.1 g), after purification by     HPLC on Rp-C₁₈ silica gel.

¹H-NMR (300 MHz, CDCl₃): 0.72–1.25 (m, 8H), 1.85 (m, 1H), 2.03 (m, 1H), 2.34 (m, 1H), 2.4 (s, 6H), 3.51–3.77 (m, 3H), 3.8 (s, 3H), 6.36 (s, 1H), 6.7 (s, 1H), 6.86 (d, J=8.8, 2H), 7.23–7.29 (m, 5H), 7.56 (d, J=5.3, 2H). LC-MS¹: t_(R)=0.97 min, [M+1]⁺=533.

Example 221

-   a)     (±)-(1R*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is isolated as a second product in step c) in Example 171. LC-MS¹:     t_(R)=1.24 min, [M+1]⁺=555.06. -   b)     (±)-(1R*,9bS*)-8-chloro-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclo-buta[c]cycloheptene-2,4-dione     is treated with LiOH.H₂O as described in Example 25 to furnish     (±)-(R*)-[(5S*)-7-chloro-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid. LC-MS¹: t_(R)=1.09 min, [M+1]⁺=573.09. The material is not     identical to the product isolated in Example 171.

Example 222

-   a) A freshly prepared solution of propyl magnesiumbromide (prepared     from magnesium (5.35 g, 0.22 mol) and 1-bromopropane (29.53 g, 0.24     mol)) in THF (200 ml) is slowly added at −70° C. to a solution of     3-bromobenzylbromide (50 g, 0.2 mol) in THF (100 ml). During the     addition the temperature is kept below −60° C. To the resulting     suspension Li₂CuCl₄ (10 ml of 0.1 M solution in THF) is added. The     reaction mixture is allowed to come slowly to rt, and an exothermic     reaction starts. The temperature reaches 40° C. and the mixture is     again cooled to 10° C. The dark suspension is stirred for 2 h before     it is treated with sat. aq. NH₄Cl (100 ml). Stirring is continued     for 20 min, the mixture is diluted with diethyl ether and water, the     organic phase is separated and washed with brine. The dark blue aq.     phase is extracted once more with diethyl ether. The combined     organic phase is dried over MgSO₄ and evaporated. The crude product     was purified by column chromatography on silica gel eluting with     hexane to furnish 1-bromo-3-butyl-benzene (16.42 g) as a colourless     oil.

¹H-NMR (300 MHz, CDCl₃): 0.94 (t, J=7.6, 3H), 1.36 (oct, J=7.6, 2H), 1.52–1.65 (m, 2H), 2.59 (t, J=7.6, 2H), 7.07–7.16 (m, 2H), 7.27–7.34 (m, 2H).

-   b)     (±)-(S*)-[(5S*)-5-(3-Butyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic     acid is prepared starting from 1-bromo-3-butyl-benzene in analogy to     Example 193. LC-MS¹: t_(R)=1.17 min, [M+1]⁺=595.28.

Example 223 to 229

The following examples are prepared starting from (±)-(1S*,9bS*)-9b-(3-butyl-phenyl)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5-(4-methoxy-benzyl)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione (Example 222) in analogy to the procedures given in Example 48:

t_(R) (LC-MS¹) Example R [min] [M + 1]⁺ 223

1.39 621.33 224

1.20 619.24 225

1.27 633.17 226

1.18 619.21 227

1.23 619.21 228

1.22 619.19 229

1.21 619.20

Example 230

A solution of (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-5-yl]-acetic acid (150 mg, 0.266 mmol, Example 107) in DMF (5 ml) is treated with triethylamine (162 mg, 1.60 mmol) and 2-chloro-dimethylacetamide (162 mg, 1.38 mmol). The mixture is stirred at rt for 18 h before it is diluted with EA, washed twice with water, dried over MgSO₄ and evaporated. The crude product is purified by chromatography on prep. tlc plates (DCM with 10% methanol) and crystallisation from diethyl ether/hexane to give (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid dimethylcarbamoylmethyl ester (151 mg) as a white powder. LC-MS¹: t_(R)=1.10 min, [M+1]⁺=648.15. 

1. A compound of Formula 1,

wherein X represents —CH₂—CH₂—CH₂—; —NR⁹—C(═O)—CH²—; —NR¹⁰—CH₂—CH₂—; —C(═O)—CH₂—CH₂—; —CH₂—C(═O)—CH₂—; —O—CH₂—CH₂—; —S—CH₂—CH₂; —SO₂—CH₂—CH₂—; —NR⁹—C(═O)—CH₂—CH₂—; —NR¹⁰—CH₂—CH₂—CH₂—; —O—CH₂—CH₂—CH₂—;

Y represents O; S; NH; N—CH₃ or CH₂; R¹, R², R³, R⁴ represent hydrogen; or one or two of R¹, R², R³, R⁴ independently represent halogen; hydroxy; lower alkyl; lower alkyloxy; lower alkyloxycarbonyl; hydroxy carbonyl; amino; lower alkylamino; di-(lower alkyl)-amino; lower alkylcarbonylamino; or trifluoromethyl; and the others are hydrogen; R⁵ represents hydrogen; lower alkyl; phenyl; mono-, di-, or tri-substituted phenyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; mono- or di-substituted phenyl, substituted with trifluoromethyl; pyridyl; benzyl or mono- or disubstituted benzyl, substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, or lower alkylthio; R⁶ represents phenyl; mono-, di-, or tri-substituted phenyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, lower alkylthio, alkylene-dioxy, or ethylenoxy; mono- or di-substituted phenyl, substituted with trifluoromethyl; pyridyl; mono- or di-substituted pyridyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, or lower alkylthio; pyrimidinyl; mono- or di-substituted pyrimidinyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; or mono-substituted pyrimidinyl, substituted with trifluoromethyl; R⁷ represents hydrogen; lower alkyl; cycloalkyl; lower alkylcarbonyl; benzyl; or optionally substituted benzyl, substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy, or ethylenoxy; R⁸ represents hydrogen; lower alkyl; or lower alkylcarbonyloxy-lower alkyl; R⁹ represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; hydroxycarbonyl-lower alkyl whereby lower alkyl can be substituted with phenyl; lower alkyloxycarbonyl-lower alkyl whereby lower alkyl can be substituted with phenyl; tetrazol-5-yl-lower alkyl; 2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl; 2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl-lower alkyl; 2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl; 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl-lower alkyl; amino-lower alkyl; lower alkylamino-lower alkyl; di-(lower alkyl)-amino-lower alkyl; aminocarbonyl-lower alkyl; lower alkylamino carbonyl-lower alkyl; di-(lower alkyl)-aminocarbonyl-lower alkyl; hydroxy-lower alkyl; lower alkyloxy-lower alkyl; benzyl; or mono- or di-substituted benzyl substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy, or ethylenoxy; R¹⁰ represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; hydroxycarbonyl-lower alkyl whereby lower alkyl can be substituted with phenyl; lower alkyloxycarbonyl-lower alkyl whereby lower alkyl can be substituted with phenyl; tetrazol-5-yl-lower alkyl; 2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl; 2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl-lower alkyl; 2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl; 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl-lower alkyl; amino-lower alkyl; lower alkylamino-lower alkyl; di-(lower alkyl)-amino-lower alkyl; aminocarbonyl-lower alkyl; hydroxy-lower alkyl; lower alkyloxy-lower alkyl; benzyl; mono- or di-substituted benzyl substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy, or ethylenoxy; benzylcarbonyl; mono- or di-substituted benzylcarbonyl substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy, or ethylenoxy; lower alkylcarbonyl; phenylcarbonyl; mono- or di-substituted phenylcarbonyl substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy, or ethylenoxy; lower alkylcarbonyl; lower alkyloxy-lower alkylcarbonyl; or hydroxycarbonyl-lower alkylcarbonyl; R¹¹ represents hydrogen; lower alkyl; cycloalkyl; lower alkyloxy-lower alkyl; lower alkyloxycarbonyl; hydroxycarbonyl; lower alkyloxycarbonyl-lower alkyl; hydroxycarbonyl-lower alkyl; phenyl; mono- or di-substituted phenyl substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, or lower alkylthio; benzyl; or mono- or di-substituted benzyl substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; R¹² represents hydrogen; lower alkyl; cycloalkyl; lower alkyloxy-lower alkyl; phenyl; or mono- or di-substituted phenyl substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, or lower alkylthio; R¹³ represents hydrogen; lower alkyl; cycloalkyl; or lower alkyloxy-lower alkyl; R¹⁴ represents hydrogen; lower alkyl; cycloalkyl; lower alkyloxy-lower alkyl; phenyl; mono- or di-substituted phenyl substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, or lower alkylthio; benzyl; mono- or di-substituted benzyl substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; lower alkyloxycarbonyl; hydroxycarbonyl; lower alkyloxycarbonyl-lower alkyl; hydroxycarbonyl-lower alkyl lower; aminocarbonyl; alkylaminocarbonyl; or di-(lower alkyl)-aminocarbonyl; and R¹⁵ represents hydrogen; lower alkyl; cycloalkyl; lower alkyloxy-lower alkyl; lower alkyloxycarbonyl; hydroxycarbonyl; lower alkyloxycarbonyl-lower alkyl; hydroxycarbonyl-lower alkyl; aminocarbonyl; lower alkylaminocarbonyl; or di-(lower alkyl)-aminocarbonyl, or an optically pure enantiomer, a mixture of enantiomers, a racemate, a pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates, a meso-form, or a pharmaceutically acceptable salt thereof.
 2. A compounds of claim 1, wherein R⁶ represents pyrimidinyl; mono- or di-substituted pyrimidinyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; or mono-substituted pyrimidinyl, substituted with trifluoromethyl, and Y represents oxygen, or a pharmaceutically acceptable salt thereof.
 3. A compounds of claim 1, wherein R⁵ represents phenyl; mono-, di-, or tri-substituted phenyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; or mono-, or di-substituted phenyl, substituted with trifluoromethyl, or a pharmaceutically acceptable salt thereof.
 4. A compounds of claim 1, wherein X represents —NR⁹—C(═O)—CH₂—, or a pharmaceutically acceptable salt thereof.
 5. A compounds of claim 1, wherein R² represents hydrogen, or a pharmaceutically acceptable salt thereof.
 6. A compounds of claim 1, wherein R¹ represents hydrogen, R² represents hydrogen, and R⁴ represents hydrogen, or a pharmaceutically acceptable salt thereof.
 7. A compounds of claim 1, wherein R¹ represents hydrogen, R² represents hydrogen, R³ represents hydrogen or halogen, and R⁴ represents hydrogen, or a pharmaceutically acceptable salt thereof.
 8. A compounds of claim 1, wherein R¹ represents hydrogen, R² represents hydrogen, R³ represents hydrogen or halogen, R⁴ represents hydrogen, R⁵ represents phenyl; mono-, di-, or tri-substituted phenyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; or mono- or di-substituted phenyl, substituted with trifluoromethyl, R⁶ represents pyrimidinyl; mono- or di-substituted pyrimidinyl, substituted with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, or lower alkylthio; or mono-substituted pyrimidinyl, substituted with trifluoromethyl, R⁷ represents hydrogen, R⁸ represents hydrogen, R⁹ represents lower alkyl; lower alkenyl; lower alkynyl; hydroxycarbonyl-lower alkyl whereby lower alkyl can be substituted with phenyl; lower alkyloxycarbonyl-lower alkyl whereby lower alkyl can be substituted with phenyl; hydroxy-lower alkyl; lower alkyloxy-lower alkyl; tetrazol-5-yl-lower alkyl; 2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl; 2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl-lower alkyl; 2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl-lower alkyl; 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl-lower alkyl; benzyl; or mono- or di-substituted benzyl substituted at the phenyl ring with lower alkyl, lower alkyloxy, halogen, amino, lower alkylamino, di-(lower alkyl)-amino, trifluoromethyl, lower alkylthio, alkylene-dioxy, or ethylenoxy, X represents —NR⁹—C(═O)—CH₂—, and Y represents oxygen, or a pharmaceutically acceptable salt thereof.
 9. A Compound selected from the group consisting of: (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((6S*)-1-methyl-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((6S*)-6-phenyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[c]azulen-6-yl)-acetic acid; (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid; (±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethoxy-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid methyl ester; (±)-(S*)-(4,6-dimethoxy-pyrimidin-2-yloxy)-[(5S*)-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid; (±)-(S*)-((5S*)-1-Carboxymethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-1-(3,5-Dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-Dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(1H-tetrazol-5-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-4-{(5S*)-5-[(S*)-Carboxy-(4,6-dimethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid methyl ester; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(4-trifluoromethyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-1-(3-chloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-{(5S*)-1-[2-(1-methyl-1H-indol-3-yl)-ethyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl}-acetic acid; (±)-(S*)-[(5S*)-1-(2-chloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-(5S*)-2-oxo-1-phenethyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(4-trifluoromethoxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-1-(2,6-difluoro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-{(5S*)-1-[2-(2-methoxy-ethoxy)-ethyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl}-acetic acid; (±)-(S*)-[(5S *)-1-(2,4-difluoro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,3,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trimethyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,3,4-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-1-(4-butyl-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-1-(2,6-dichloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-2-oxo-1,5-diphenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid; (±)-4-{(5S*)-5-[(S*)-carboxy-(4,6-diethyl-pyrimidin-2-yloxy)-methyl]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-ylmethyl}-benzoic acid methyl ester; (±)-(S*)-(4,6-diethyl-pyrimidin-2-yloxy)-[(5S*)-1-(2-hydroxy-ethyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-diethyl-pyrimidin-2-yloxy)-[(5S*)-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-diethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-4-methyl-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-7-chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(3,5-dimethoxy-phenoxy)-acetic acid; (±)-(1S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid; (±)-(1S*)-[(5S*)-7-chloro-1-(3,5-dimethoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethoxy-pyrimidin-2-yloxy)-acetic acid; (±)-(1S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetra-hydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-7-chloro-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-1-(4-butylbenzyl)-7chloro-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-7-chloro-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-7-chloro-1-(2,6-dichloro-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-((5S*)-7-chloro-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-diethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-2-oxo-5-m-tolyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-2-oxo-1-(2,4,6-trimethyl-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-2-oxo-1-(2,3,4-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-ethyl-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-1-(4-methoxy-benzyl)-5-(3-methoxy-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-methoxy-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-1-carboxymethyl-5-(3-methoxy-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(3-methoxy-phenyl)-2-oxo-1-(2,3,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-5-biphenyl-3-yl-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-((5S*)-5-biphenyl-3-yl-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-((5S*)-5-biphenyl-3-yl-1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-5-biphenyl-3-yl-2-oxo-1-(2,3,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-5-(4-fluoro-3-methyl-phenyl)-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid; (±)-(S*)-[(5S*)-5-butyl-1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(R*)-[(5S*)-7-chloro-1-(4-methoxy-benzyl)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-1-(4-butyl-benzyl)-5-(3-butyl-phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-5-(3-butyl-phenyl)-2-oxo-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; (±)-(S*)-[(5S*)-5-(3-Butyl-phenyl)-1-(2,6-dichloro-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; and (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-[(5S*)-2-oxo-5-phenyl-1-(2,4,6-trifluoro-benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid dimethylcarbamoylmethyl ester, or a pharmaceutically acceptable salt thereof.
 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 and a pharmaceutically acceptable carrier and/or an adjuvant.
 11. A process for the manufacture of a compound as claimed in any one of claims 1 to 9, which process comprises: a) in case Y represents CH₂ and R⁶ represents phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, or substituted pyrimidinyl, in Formula I, reacting a compound of Formula IV with an ester of a compound of Formula V in the presence of a strong base, b) in case Y represents N—CH₃ and R⁶ represents phenyl or substituted phenyl in Formula I, reacting a compound of Formula IV with an ester of a compound of Formula V in the presence of a strong base, c) in case Y represents O or S and R⁶ represents phenyl or substituted phenyl in Formula I, reacting a compound of Formula IV with a compound of Formula V in the presence of a base and an activating agent, d) in case Y represents NH and R⁶ represents phenyl or substituted phenyl in Formula I, reacting a compound of Formula IV with a compound of Formula V, wherein NH is previously derivatized with a protective group, in the presence of a base and an activating agent, and subsequently deprotecting the amine,

e) in case Y represents O, S, NH or N—CH₃ and R⁶ represents a pyridinyl, a substituted pyridinyl, a pyrimidinyl or a substituted pyrimidinyl group, in Formula I, reacting a compound of Formula VIII with a compound of Formula VII, wherein G¹ represents a reactive group, in the presence of a base,

f) cleaving the protecting group P² in a compound of Formula IX which is prepared by reacting a compound of Formula IV with a compound of Formula X,

g) reacting a compound of the Formula III with water or an alcohol R⁸—OH in the presence of either a base or an acid in the presence or absence of an additional solvent at a temperature between zero and 100° C.,

h) in case R⁷ in Formula I does not represent a hydrogen atom, reacting a compound of Formula II with an alkylating or acylating agent R⁷—G¹, wherein G¹ represents a reactive group, in order to obtain a compound of Formula I, wherein R⁷ does not represent a hydrogen atom and wherein R⁸ represents a lower alkyl group, or i) reacting a compound of Formula II

wherein R⁸ represents a lower alkyl group, in water in the presence of a base or an acid in the presence or absence of an additional solvent to obtain a compound of Formula I, wherein R⁷ does not represent a hydrogen atom and wherein R⁸ represents a hydrogen atom.
 12. A process for manufacturing a pharmaceutical composition according to claim 10, comprising mixing one or more of the compounds with a pharmaceutically acceptable excipient. 